The syntheses of bis guanidium salts and their applications in asymmetric mukaiyama type SN2 alkylation reactions

... The Syntheses of Various Bis- Guanidium Salts Chapter The Syntheses of Various Bis- Guanidium Salts Chapt r 1: The Syntheses of Various Bis- Guanidium Salts 11 Chapter The Syntheses of Various Bis- Guanidium. .. Pentanidium Salts to Bis- Guanidium Salts 1.2 Syntheses of Various Bis- Guanidium Salts Since the basic fragments of bis- guanidium salts are the same as those of pentanidium salts, the synthetic procedure... in MeCN can provide the bis- guanidium salts with good overall yield in to steps 30 Chapter The Syntheses of Various Bis- Guanidium Salts Scheme 1.22 Standrad Procedure of Bis- guanidium Salts Syntheses

THE SYNTHESES OF BIS-GUANIDIUM SALTS AND THEIR APPLICATIONS IN ASYMMETRIC MUKAIYAMA TYPE SN2 ALKYLATION REACTIONS DONG SHENG (BSc., Zhejiang University) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2014 To my family for their love, support, and encouragement Acknowledgements It is hard for me to express myself in English, but I know I have to. This is the only and the best chance for me to show all my gratitude, to everyone and everything appeared in my past three years. Firstly, I need to thank all my families in China for everything they did in the past 27 years. They built my world with their hands, their hearts and their love. I wouldn’t be the happiest guy in this world if any of them is absent for even a single second. They would never know about this, because none of them knows English very well and I won’t translate this part to them. LOL. Secondly, I need to thank my beloved Ms. Jiang Xiang’er for her love and understanding in last year and endless time in future. I will take her to a French restaurant when I get my degree if she pays the bill. Thirdly, I want to thank my supervisor, Associate Professor Tan Choon Hong. He brought me to Singapore, and taught me a lot of things about chemistry and life which may help me to be survived on this island. Last but not the least, I want to thank all my friends, in Singapore and any other places. I won’t list their names, since that list would be too long. But you will always be there, in my heart. Content Summary ................................................................................................................... 1 List of Tables ............................................................................................................. 2 List of Figures ............................................................................................................ 3 List of Schemes.......................................................................................................... 4 List of Abbreviations ................................................................................................. 8 Chapt r 1: The Syntheses of Various Bis-Guanidium Salts ...................................... 11 1.1 Introduction to Asymmetric Phase-Transfer Catalysis....................................... 12 1.1.1 General Introduction ........................................................................... 12 1.1.2 Previous Reports with Different Types of Chiral PTCs ..................... 14 1.2 Syntheses of Various Bis-Guanidium Salts ......................................................... 30 1.3 Summary ............................................................................................................ 34 References ................................................................................................................ 35 Chapter 2: Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compounds .................................................................. 39 2.1 Introduction of Asymmetric Organocatalysis of Chiral Quaternary Ammonium Fluorides ................................................................................................................... 40 2.1.1 General Introduction ........................................................................... 40 2.1.2 Previous Reports with Chiral Quaternary Ammonium Fluorides....... 40 1 2.1.3 Conclusion .......................................................................................... 51 2.2 Brief Introduction of Asymmetric Organocatalysis of 1,4-Dicarbonyl Compounds .............................................................................................................. 52 2.2.1 Brief Introduction................................................................................ 52 2.2.2 Conclusion .......................................................................................... 59 2.3 Fluoride Anions Mediated Enantioselective Mukaiyama Type SN2 Alkylation Reaction Catalyzed by Bis-Guanidium Salts. ............................................................ 60 2.3.1 Trigger of the Project .......................................................................... 60 2.3.2 Guanidium Salts Catalyzed Asymmetric SN2 Alkylation Reaction.... 61 2.3.3 Conclusion .......................................................................................... 87 References ................................................................................................................ 88 Chapter 3: The Experimental Procedures ............................................................... 91 3.1 General Information ........................................................................................... 92 3.2 Syntheses and Characterizations of Chiral Bis-Guanidium Salts........................ 93 3.3 Representative Procedure for Asymmetric Mukaiyama Type SN2 Alkylation Reactions of Silyl Compounds and α-Bromoesters ................................................ 104 Appendices............................................................................................................ 109 2 Summary In this study, we designed and successfully synthesized a new type of phase-transfer catalysts with full alkylated guanidiums as functional centers and applied these catalysts in asymmetric catalysis of 1,4-dicarbonyl compounds via Mukaiyama type SN2 alkylation reactions. Firstly, a series of bis-guanidium salts were synthesized from commercially available and cheap chiral sources in 4 to 5 steps. For most of the derivatives, the overall yields were good. Synthetic problems were met when the catalysts were highly sterically hindered or strong electron withdrawing. Then, these chiral bis-guanidium salts were tested in asymmetric Mukaiyama type SN2 alkylation reactions as phase-transfer catalysts. Up to 86% ee was obtained, and for most of the substrates, the yields were good. Two catalytic systems were studied, and each of them had their advantages and disadvantages. At the last of this work, suggestions to further improvement were proposed and detailed experimental procedures were provided. 1 List of Tables Table 1.1. Bis-Guanidium Salts Synthesized from Standard Procedure and Its Modified Versions. Table 2.1. Order of Lipophilicities of Anions. Table 2.2. First Round of Catalyst Screening Results of the Model Reaction. Table 2.3. Preliminary Screening of Solvents and Fluoride salts. Table 2.4. Screening of Fluoride Salts with the Model Reaction. Table 2.5. Screening of Different Cesium Salts as Additives in the Model Reaction. Table 2.6. Testing of Different Loadings of CsOAc in the Model Reaction. Table 2.7. Catalyst Screening of Bis-Guanidium Salts with the Model Reaction. Table 2.8. Substrate Scope Using Mixture of AgF and CsOAc as Fluoride Source. Table 2.9. Optimization Using TMAF as Fluoride Source. Table 2.10. Effects of Different Silyl Protecting Groups on the Model Reaction. Table 2.11. Effect of Mixed Solvents on the Model Reaction. Table 2.12. Effects of AgF with Different Ligands on the Model Reaction. Table 2.13. Full List of Catalysts Used in Chapter 2. 2 List of Figures Figure 1.1. Interfacial Mechanism of Phase-Transfer Catalysis Proposed by Makosza. Figure 1.2. The Dipole-Dipole Interaction of the Zwitterionic Species with Dimethylsulfonium Methylide. Figure 1.3. From Guanidine to Pentanidine and Pentanidium Salt. Figure 1.4. From Pentanidium Salts to Bis-Guanidium Salts. Figure 1.5. Imidazoline Salts of Highly Steric Hindrance which were failed to Couple with Piperizine. Figure 2.1. Hoffman Elimination of Tetraalkylammonium Fluoride Salt. Figure 2.2. Concept of SOMO Catalysis. Figure 2.3. Proposed two catalysts relay system. 3 List of Schemes Scheme1.1. Extraction Mechanism of Phase-Transfer Catalysis Proposed by Starks. Scheme 1.2. Preparation of Ephedrine Derived Chiral Phase-Transfer Catalyst. Scheme 1.3. Corey-Chaykovsky Reaction Catalyzed by Ephedrine Derived PTC. Scheme 1.4. Ephedrine Derived PTC Catalyzed Highly Enantioselective Epoxidation of Aldehyde Scheme 1.5. Alkylation Reactions Catalyzed by Ephedrine Derived PTC. Scheme 1.6. N-Alkylation Reaction to Synthesize Alkaloid Derived PTC. Scheme 1.7. Alkylation of Indanone Catalyzed by Alkaloid Derived PTC. Scheme 1.8. Asymmetric Monoalkylation of 17 Catalyzed by Alkaloid Derived PTC. Scheme 1.9. Professor Lygo’s PTC Catalyzed Alkylation of 17. Scheme 1.10. Corey’s Alkaloid Derived PTC Catalyzed Monoalkylation of 17. Scheme 1.11. Asymmtric Alkylation of 17 Catalyzed by Maruoka’s Chiral Spiroammonium Salts Type of PTC. Scheme 1.12. Asymmetric Alkylation of 17 Catalyzed by Chiral Guanidium Type of PTC. Scheme 1.13. Asymmetric Alkylation of 17 Catalyzed by Flexible C3-Symmetric Chiral PTC. Scheme 1.14. Asymmetric Alkylation of 17 Catalyzed by Chiral Bis(spiroammonium) 4 Salt as a Phase-Transfer Catalyst. Scheme 1.15. Tartrate-Derived Linear Chiral PTC Catalyzed Alkylation of 17. Scheme 1.16. Tartrate-Derived Cyclic Chiral PTC Catalyzed Alkylation of 17. Scheme 1.17. Michael Addition to Acrylates Catalyzed by Chiral Crown Complexes. Scheme 1.18. Synthesis of Full Methylated Pentanidium Salt. Scheme 1.19. Pentanidium-Catalyzed Conjugate Addition of Schiff Base 17 to 42. Scheme 1.20. Pentanidium-Catalyzed Asymmetric α-Hydroxylation Reaction of 44. Scheme 1.21. Asymmetric Conjugate Addition Reactions Catalyzed by PTC 25. Scheme 1.22. Standard Procedure of Bis-guanidium Salts Syntheses. Scheme 1.23. Mono-Coupling of Imidazoline Salt 48b with Linker 49 due to the Electronic Effect. Scheme 2.1. Asymmetric Conjugation Addition of Nitromethane to Chalcone Catalyzed by In Situ Formed Chiral Quaternary Ammonium Fluorides. Scheme 2.2. Counterion Effect of the Catalyst in Mukaiyama Aldol Reaction. Scheme 2.3. Cyclic Type of Asymmetric Mukaiyama Aldol Reaction. Scheme 2.4. Alkylative Kenetic Resolution of Secondary Alkyl Halides. Scheme 2.5. Methods of Counterion Exchange from Bromide to Fluoride. Scheme 2.6. Linear Type of Asymmetric Mukaiyama Aldol Reaction. Scheme 2.7. Asymmetric Vinlogous Mukaiyama Aldol Reaction. 5 Scheme 2.8. Asymmetric Trifluoromethylation of Aromatic Aldehyde and Ketones. Scheme 2.9. Asymmetric Reduction of Ketones with Alkoxysilanes. Scheme 2.10. Asymmetric Synthesis of α-Amino Acid via Mukaiyama Aldol Reaction. Scheme 2.11. Asymmetric Mukaiyama Type Nitroaldol Reaction. Scheme 2.12. Asymmetric Michael Addition of TMS-Protected Nitroethane to trans-Cinnamaldehyde. Scheme 2.13. Concept of Asymmetric Hydrogenation of Dimethyl Itaconate with Flow Reactor. Scheme 2.14. First Asymmetric Intramolecular Stetter Reaction. Scheme 2.15. Selected Example of First Successful Asymmetric Intermolecular Stetter Reaction. Scheme 2.16. First Asymmetric Intermolecular Stetter Reaction with Excellent Enantioselectivity. Scheme 2.17. Application of Asymmetric Intermolecular Stetter Reaction in the Synthesis of Enantioenriched α-Amino Acid Derivatives. Scheme 2.18. Enantioselective Intermolecular Stetter Reactions on β-Aryl Substituted Acceptors. Scheme 2.19. Asymmetric Stetter type Michael addition of enals to modified chalcones. 6 Scheme 2.20. Asymmetric SOMO Catalysis of 1,4-Dicarbonyl Compounds. Scheme 2.21. Photocatalysis Version of SOMO catalysis. Scheme 2.22. Enantioselective Aza-Ene Type Reaction Catalyzed by Chiral N,N’-Dioxide-Nickel(II) Complex. Scheme 2.23. Enantioselective Conjugate Addition Reaction of 1,4-Dicarbonyl But-2-Enes to Synthesize α-Stereogenic Amides and Ketones. Scheme 2.24. Failed Attempts of OH- Mediated Alkylation Reactions. Scheme 2.25. Model Reaction of Mukaiyama Type SN2 Alkylation Reaction. Scheme 2.26. Proof of Anion Exchange in Solid Phase. Scheme 2.27. Results of Modification on Ester Part for the Model Reaction. Scheme 2.28. Effects of the Leaving Groups on the Model Reaction. Scheme 2.29. Finalized Reaction Condition to the Model Reaction Using Mixture of AgF and CsOAc as Fluoride Source. Scheme 2.30. Bis-Guanidium Catalyzed Asymmetric Mukaiyama SN2 Alkylation Reaction with α-Bromo t-Butylacetate. Scheme 2.31. Improvement on Ee Values by Tuning the Catalysts. 7 List of Abbreviations AcOH acetic acid [] optical rotation aq. aqueous Bn benzyl t-Bu tert-butyl o degrees (Celcius)  chemical shift in parts per million DCM dichloromethane DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide dd doublet of doublet d day(s) ee enantiomeric excess ESI electro spray ionization Et ethyl EtOH ethanol g grams hr hour(s) C 8 equiv. equivalent HPLC high pressure liquid chromatography HRMS high resolution mass spectroscopy Hz hertz IPA isopropanol J coupling constant KHMDS potassium bis(trimethylsilyl)amide LHMDS lithium bis(trimethylsilyl)amide Me methyl MeCN acetonitrile MeOH methanol mg milligram MHz megahertz min. minute(s) mL milliliter L microliter mmol millimole MS mass spectroscopy NMR nulcear magnetic resonance n.d. Not determined n.p. No product 9 n.r. No reaction Ph Phenyl iPr isopropyl ppm parts per million PTC Phase-transfer catalyst TMS Trimethyl silyl TES Triethyl silyl TBS Di(methyl)tert-butyl silyl r.t. room temperature THF tetrahydrofuran TLC thin layer chromatography TBAB tetra-n-Butylammonium bromide TBAF tetra-n-Butylammonium fluoride TBME tert-Butyl methyl ether TFA trifluoroacetic acid TMAB tetramethyl ammonium bromide TMAF tetramethyl ammonium fluoride Boc tert-Butyloxycarbonyl M mol∙L-1 mM mmol∙L-1 10 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Chapter 1 The Syntheses of Various Bis-Guanidium Salts Chapt r 1: The Syntheses of Various Bis-Guanidium Salts 11 Chapter 1. The Syntheses of Various Bis-Guanidium Salts 1.1 Introduction to Asymmetric Phase-Transfer Catalysis 1.1.1 General Introduction Phase-transfer catalysts (PTCs) are chemical agents that facilitate the transfer of a molecule or ion from one reaction phase to another and in doing so can greatly accelerate the rate of heterogeneous (polyphasic) reaction processes.1-3As the concept declares, phase-transfer catalysts can help to transfer a reagent or ion from one phase to the other and enhance the reactivity. In the middle to late 1960s, Starks, Makosza and Brandstorm discovered and built the foundation of phase transfer reactions.4,5 Based on their own research data and phenomena, Starks and Makosza proposed different mechanisms both of which are generally accepted nowadays. Makosza proposed the interfacial mechanism (Figure 1.1), which means the exchange of the counter ions happen at the interface of two immiscible phases, and PTCs cannot enter the aqueous phase. Figure 1.1. Interfacial Mechanism of Phase-Transfer Catalysis Proposed by Makosza. Starks proposed a different mechanism which is known as extraction mechanism. For example, in 1971, Starks did the SN2 reaction of 1-chlorooctane (starting material and organic phase) with NaCN aqueous solution catalyzed by 12 Chapter 1. The Syntheses of Various Bis-Guanidium Salts hexadecyltributylphosphonium bromide (Scheme 1.1). The catalyst could distribute in both organic and aqueous layers, and exchanged the anions in the aqueous phase and took them back to the organic phase. Without the phosphosium salt as the catalyst, there was no reaction even in a prolonged reaction time. In this case, the term of “phase-transfer catalysis” was first introduced to explain the reaction phenomenon and the important role of ammonium or phosphonium salts in this heterogeneous system.4 Scheme1.1. Extraction Mechanism of Phase-Transfer Catalysis Proposed by Starks. Both of these two mechanisms can be true due to different reaction conditions. 6 Because of the bulkiness of asymmetric PTCs, almost all the catalysts undergo the Makosza pathway. Compared with homogeneous reactions, phase-transfer catalysis has several unique advantages in application:7  The anion reactivities of both Q+R- and Q+OH- (in Starks pathway) are increased due to larger separation of charges and reduced number of hydration, which results in higher reaction rate than that of homogeneous media.  Phase-transfer catalysis usually show better selectivity than homogeneous reactions due to the milder conditions applied and controllable delivery of 13 Chapter 1. The Syntheses of Various Bis-Guanidium Salts reactive reagent to the target phase, even sometimes show different chemoselectivity.  The workup procedures of phase-transfer catalysis are generally much easier than homogeneous reactions, due to many of the byproducts and reagents may be in aqueous phase, which may also be easier to recover starting materials and make it more applicable to industry. Due to the advantages mentioned above, phase-transfer catalysis has been widely applied in organic syntheses for the last 30 years,1-3 and has been recognized as an important branch of “green chemistry”, which is sure the future direction of modern organic chemistry development. 1.1.2 Previous Reports with Different Types of Chiral PTCs The first example of enantioselective phase-transfer reactions was reported by Tamejiro Hiyama and his coworkers in 1974.8 The catalysts were synthesized from chiral ephedrine, and after several steps, a series of chiral PTCs were obtained which are shown in Scheme 1.2 and Scheme 1.3. They applied these catalysts to Corey-Chaykovsky epoxidation reaction. As shown in Scheme 1.3, ee values obtained from different catalysts were greatly different, and the hydroxyl group on benzyl position was important for high ee induction. Scheme 1.2. Preparation of Ephedrine Derived Chiral Phase-Transfer Catalyst. 14 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.3. Corey-Chaykovsky Reaction Catalyzed by Ephedrine Derived PTC. According to the author’s proposed mechanism, the chiral induction should be related to the zwitterionic species 6 and 7 formed in organic layer (Figure 1.2). The dipole-dipole interaction between 4 and the catalyst could form a strong chiral complex so that the ylide attacked will prefer one of the enantiotopic faces of 3. Figure 1.2. The Dipole-Dipole Interaction of the Zwitterionic Species with Dimethylsulfonium Methylide. Solvent effect was studied then. They found that PTC1 in polar solvents like THF (66% yield, 9% ee) and MeCN (48% yield, 0% ee) could not provide the results as good as those in nonpolar solvents due to the larger polarity of solvents might destroy the dipole-dipole interaction between the substrate and the catalyst. Further optimization 15 Chapter 1. The Syntheses of Various Bis-Guanidium Salts showed that the enantiomeric excess could be improved to 97% by using benzene as the solvent and PTC2 as the catalyst. Also the catalyst loading might affect the ee value greatly. Optimized results are presented in Scheme 1.4. Scheme 1.4. Ephedrine Derived PTC Catalyzed Highly Enantioselective Epoxidation of Aldehyde. Using the same type catalyst as PTC1, Fiaud finished the alkylation reaction of ethyl 2-oxocyclohexanecarboxylate in 1975.9 The precise ee values were not presented, due to the lack of chiral HPLC analysis at that time and the lack of optically pure products for optical rotation measurements. But based on the 1H NMR spectroscopy of the mixture of compound 10b and a chiral shift reagent Eu(tfacCam)3, around 5%-6% ee can be evaluated. Optimization showed that a higher catalyst loading could not increase the enantiomeric excess. More reaction results are presented in Scheme 1.5 below. 16 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.5. Alkylation Reactions Catalyzed by Ephedrine Derived PTC. In 1984, Dolling and his coworkers refluxed cinchona alkaloid with benzyl halide, and synthesized the first cinchona alkaloids derived chiral PTC, the family of which turned out to be the most successful PTCs in this research area (Scheme 1.6).10 The catalyst then was tested on the alkylation reaction of substituted indanone. Excellent ee value and yield were obtained. Further application studies transformed the compound 16 into a bioactive molecule, (+)-indacrinone (Scheme 1.7). Scheme 1.6. N-Alkylation Reaction to Synthesize Alkaloid Derived PTC. Detailed studies showed that the ee value could be higher in nonpolar solvents, such as toluene and benzene, than relative polar solvents like DCM and TBME. Dilution might help to increase the ee value, too. Different concentrations of NaOH solutions 17 Chapter 1. The Syntheses of Various Bis-Guanidium Salts were screened and 50% NaOH (aq.) gave the best results. Different catalyst loadings might result in different reaction rates, but showed no direct relation with ee value of the product. Scheme 1.7. Alkylation of Indanone Catalyzed by Alkaloid Derived PTC. In 1989, inspired by Dolling’s previous result, Donnell modified the cinchona alkaloid and got the chiral PTC9, and applied it in the enantioselective synthesis of amino acid 20 (Scheme 1.8).11 It was easier to obtain (R)-19 in good yield and moderate ee, and with PTC 10, the enantiomer of PTC 9, (S)-19 can also be synthesized. Although the ee values of the product were not high enough to be used directly, the ee could be simply increased to >99% by a single recrystalization with 50% overall yield. Further optimization showed that if the hydroxyl group was protected with allyl group, the ee value could be further increased to 81%. 18 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.8. Asymmetric Monoalkylation of 17 Catalyzed by Alkaloid Derived PTC. It had been 8 years until the next masterpiece in the area of phase-transfer catalysis came out. In 1997, Lygo and Corey did the independent research on the asymmetric alkylation of Schiff base 17, while got the same results.12 N-anthracenylmethyl ammonium salt could be a better catalyst to the reaction than Donnell’s catalysts (Scheme 1.9). Corey suggested that the reason why 9-anthracenylmethyl group could enhance the enantioselectivity was its huge steric hindrance that could block one face of R4N+, and fix the 3D structure of functional positions. He suggested the catalyst could be easily tuned by attaching different R groups on the hydroxyl group to meet different substrates. 19 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.9. Professor Lygo’s PTC Catalyzed Alkylation of 17. To exam this analysis, Corey synthesized PTC 14 and used it in the monoalkylation of schiff base 17 (Scheme 1.10). Excellent results were obtained with different electrophiles. Scheme 1.10. Corey’s Alkaloid Derived PTC Catalyzed Monoalkylation of 17 Starting from the commercially available chiral 1,1’-bi-2-naphthol, Maruoka and his coworkers successfully synthesized chiral spiroammonium salts PTC 15 and PTC 16 in 1999.13a These rigid C2-symmetric catalysts showed great efficiency in the asymmetric alkylation of 17 (Scheme 1.11). 20 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.11. Asymmtric Alkylation of 17 Catalyzed by Maruoka’s Chiral Spiroammonium Salts Type of PTC. After screening several catalysts in this family, the author found that when Ar group on the catalyst was 3,4,5-trifluorophenyl group (PTC 15e), they could get highest ee. While compared with PTC 15b, PTC 15e showed almost no different in steric effect. So the author suggested that the electron withdrawing effect might affect the enantioselectivity significantly. Further optimization showed that the catalyst loading could be reduced to 0.2 mol% without erosing its enantioselectivity. This was a great breakthrough compared with previous high loading PTCs, because the cost of the catalyst would be much easier to be accepted by industry. After this work, more reactions have been developed using this family of chiral catalysts, such as aldol 21 Chapter 1. The Syntheses of Various Bis-Guanidium Salts reactions, Mannich reactions, epoxidation reactions and made this family of catalysts as famous as cinchona alkaloids derived PTCs.13b, 13c In 2002, Nagasawa reported enantioselective alkylation of Schiff base 17, which was generally a standard reaction to exam the efficiency of new type of catalysts. The catalyst he used was a C2-symmetric chiral cyclic guanidine (Scheme 1.12). Compared with cinchona alkaloids derived PTCs and Maruoka’s chiral PTCs, this catalyst system was not so successful due to extremely long reaction time, moderate yield and higher catalyst loading. Scheme 1.12. Asymmetric Alkylation of 17 Catalyzed by Chiral Guanidium Type of PTC. In 2003, Takabe and Mase designed and prepared a new type of chiral PTC, PTC 19.15 Tested on the model benzylation reaction, the catalyst could only provided moderate yield and ee. But there were some innovations in the catalyst design, one was the usage C3-symmetric structure rather than that of C2-symmetric; the other innovation was the great flexibility of the catalyst. Bifunctional character of the catalyst was the key to ee induction (Scheme 1.13). 22 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.13. Asymmetric Alkylation of 17 Catalyzed by Flexible C3-Symmetric Chiral PTC. In 2003, Sasai developed a new chiral bis-spiroammonium salt PTC 20 and achieved excellent ee and yield with the model reaction (Scheme 1.14).16 Scheme 1.14. Asymmetric Alkylation of 17 Catalyzed by Chiral Bis(spiroammonium) Salt as a Phase-Transfer Catalyst. Shibasaki also designed and synthesized a new chiral bis-ammonium catalyst with flexible structure PTC21 derived from tartrate, which is a quite cheaper chiral source. The author obtained excellent results in the model alkylation reaction.17 The author found that changing the counteranion of the catalyst from I- to BF4- could increase both ee and yield a little bit, which could be an evidence of counterion effect (Scheme 23 Chapter 1. The Syntheses of Various Bis-Guanidium Salts 1.15). Scheme 1.15. Tartrate-Derived Linear Chiral PTC Catalyzed Alkylation of 17. Inspired by the work of Shibasaki, MacFarland also prepared a new tartrate derived bis-ammonium PTC 22, bearing 2, 5-dimethylpyrroline motieties.18 They tested it on the model asymmetric alkylation reaction, but only low yield and low ee were obtained (Scheme 1.16). Scheme 1.16. Tartrate-Derived Cyclic Chiral PTC Catalyzed Alkylation of 17. Besides ammonium PTCs, crown ether is also a famous catalyst used in phase-transfer catalysis for its selective coordination with specific cations. Some attempts were made to synthesize chiral crown ethers. 24 Chapter 1. The Syntheses of Various Bis-Guanidium Salts In 1981, Cram develop a chiral crown ether PTC, and used it in an asymmetric Michael addition reaction shown in Scheme 1.17.19 Although the substrate scope was limited, for some specific substrates, they could obtain excellent results. While there is another great problem of chiral crown ethers that the synthesis of these catalysts are high cost and low yield till now. Scheme 1.17. Michael Addition to Acrylates Catalyzed by Chiral Crown Complexes. Till now, there have been many families of PTCs developed now. Most of them are sp3 quaternary ammonium salts. Professor Nagasawa did an interesting attempt on the development of sp2 guanidine PTC. Although the result was not as good as those of cinchona alkaloids derived catalysts or Maruoka’s rigid spiroammonium PTCs, his pioneering work proved that sp2 guanidine moieties could also be ultilized as the active part of phase-transfer catalysts, but still need to be further modified. Since our group’s long term interest in developing Brønsted base catalysts modified 25 Chapter 1. The Syntheses of Various Bis-Guanidium Salts from guanidine moieties, we tried to increase the basicity by extending three nitrogen conjugations to five nitrogen conjugations to break through the pKa barrier (Figure 1.3). So compound 37 with different R groups were synthesized and tested. But the results did not consist with our hypothesis. The basicity tended to be weaker with more conjugated nitrogen atoms and enantioselectivity of these catalysts were not good. We proposed that the lack of sterical hindrance was the main reason for this failure. With bulkier R groups, full alkylatedcompound 38 could be a better catalyst, not as a Brønsted base catalyst, but as a phase-transfer catalyst. Although over several decades, there have been many families of PTCs developed, many of them were given up after several attempts for different reasons. Only two families of PTCs are still robust now which are cinchona alkaloids derived PTCs and Maruoka’s rigid spiroammonium catalysts. But because of the nature of chemistry, no catalyst scaffold can be suitable to all substrates or all extreme reaction conditions, such as oxidation conditions and strong basic and high temperature conditions. Also the costs of Maruoka’s catalysts actually are still too high to be accepted by industry. So it is still necessary for us to develop a third type of PTCs as alternatives, especially when the costs are relatively lower. Before our work, all the guanidine based PTCs’ active parts were acid forms of guanidine (protonated guanidines), which could be surely deprotonated under basic conditions. Then the real bases that deprotonated the starting materials could be the base form of guanidines, which are weaker than inorganic bases like NaOH. So we assumed that our full alkylated pentanidium salts should at least show better reaction rates than previous guanidine based PTCs. Then we started to investigate these 26 Chapter 1. The Syntheses of Various Bis-Guanidium Salts pentanidium salts and their applications. Figure 1.3. From Guanidine to Pentanidine and Pentanidium Salt. Scheme 1.18. Synthesis of Full Methylated Pentanidium Salt. As shown above (Scheme 1.18), full methylation pentanidium PTC 24a could be easily synthesized from commercial available, cheap chiral amine 38 (2000 SGD/Kg) with high overall yield. 27 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.19. Pentanidium-Catalyzed Conjugate Addition of Schiff Base 17 to 42. In 2011, it was successfully used in enantioselective Michael addition reaction of Schiff base 17 with acrylates and chalcones (Scheme1.19). Excellent results were obtained, and reaction rate were very fast as our hypothesis. Tested on one example of 43c5, the catalyst loading could be lowered to 0.03 mol% without obvious erosion of ee value, which was a very important factor to potential industry applications. Meanwhile, our group continued to synthesize a serie of pentanidium salts with different R groups, built the catalyst library and systematically studied the properties of this catalyst family. In 2012, we used modified pentanidium salt PTC 24b to solve the asymmetric α-hydroxylation reaction of oxindoles with air (Scheme 1.20). Mechanistically, the reaction contained 2 parts: enantioselective oxidation with O2 to form chiral peroxide intermediates, and kenetic resolution reduction of peroxides with oxindole enolates. Both ee and yield were excellent. Interestingly, during the optimization, we found that when both R1 and R2 were 3, 5-di(t-Bu)C6H3CH2 group, enantioselectivity were the best, slightly better than PTC 24b, but the reaction rate would be lowered a lot. Scheme 1.20. Pentanidium-Catalyzed Asymmetric α-Hydroxylation Reaction of 44. 28 Chapter 1. The Syntheses of Various Bis-Guanidium Salts In 2013, inspired by our group’s pioneering work, Hii prepared another type of sp2 quarternary nitrogen PTCs, and tried on the asymmetric conjugate addition of 17 with different Michael acceptors (Scheme 1.21).20 Scheme 1.21. Asymmetric Conjugate Addition Reactions Catalyzed by PTC 25. Based on our own research results and previous literatures, we found that both steric and electronic effects of the R groups attached to the nitrogens had great influence on the enantioselectivity. Furthermore, the five conjugated nitrogens of our catalysts were not necessary to get excellent enantiomeric excesses in some cases. Full alkylated guanidines might be already good enough for catalysis and easier to be synthesized. We also got a hint from some of the previous literatures that they used bis-ammonium salts as phase transfer catalyst and obtained good results,16,17,18 so we decided to try to develop a new type of catalysts: full alkylated bis-guanidium PTCs (Figure 1.4). 29 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Figure 1.4. From Pentanidium Salts to Bis-Guanidium Salts. 1.2 Syntheses of Various Bis-Guanidium Salts Since the basic fragments of bis-guanidium salts are the same as those of pentanidium salts, the synthetic procedure is modified from that of pentanidium salts. Standard procedure is shown in Scheme 1.22. Urea 39 can be easily synthesized from commercial available chiral diamine 38 with triphosgen under basic conditions, and N-alkylated product 40 can be synthesized with quantitative yield. Different R groups on the nitrogen may lead to different procedure for the following steps. Methylated 40a is active enough to react with (COCl)2 to form the imdazoline intermediate. But ureas with other substituents on nitrogens (even if ethyl group) have to be further activated by transforming ureas to thioureas with Lawesson’s reagent. Compound 48, which was identified by LC-MS (ESI), was condensed with rotary evaporator and vacumn dried before being used in the next step. Column purification is not applicable due to its sensitivity of moisture. Finally, the simple reflux of 48 with 0.3 equivalent of piperazine in MeCN can provide the bis-guanidium salts with good overall yield in 4 to 5 steps. 30 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Scheme 1.22. Standrad Procedure of Bis-guanidium Salts Syntheses. With the standard procedure, different modifications on chiral backbones, R groups and central linkers were carried out, and the successfully synthesized catalysts were presented in Table 1.1. Table 1.1. Bis-Guanidium Salts Synthesized from Standard Procedure and Its Modified Versions. Entry Code：PTC 26a MW.a: 655.70 Structure Entry Code：PTC 26b MW. a: 1408.94 31 Structure Chapter 1. The Syntheses of Various Bis-Guanidium Salts Code：PTC 26c MW. a: 1801.03 Code：PTC 26d MW. a: 1160.32 Code：PTC 26e MW. a: 962.10 Code：PTC 26f MW. a:1160.32 Code：PTC 26g MW. a: 1724.52 Code：PTC 26h MW. a: 1320.40 Code：PTC 26i MW. a: 1184.51 Code：PTC 26j MW. a: 1240.62 Code：PTC 26k MW. a: 1529.04 Code：PTC 26l MW. a: 1546.72 Code: PTC26m MW. a: 1465.04 Code：PTC 26n MW. a: 1432.96 Code：PTC 26o MW. a: 1609.17 Code：PTC26p MW. a: 1537.54 32 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Code：PTC 26q MW. a: 1633.36 Code：PTC 26r MW. a: 1436.99 Code：PTC 26s a MW. : 1504.07 Code：PTC 26t MW. a: 1588.93 Code：PTC 26u MW. a: 1680.93 a The molecular weights shown in the table are calculated by ChemBioDraw Ultra 12.0 PTC 26a to PTC 26n could be easily synthesized according to the synthetic procedure with a range of 40 to 50% overall yield. But for those more sterically hindered bis-guanidiums (PTC 26o to PTC 26r), the last steps needed to be proceeded in sealed tubes at 110 oC in acetonitrile to obtained a reasonable yield (30 to 40% overall yield). For those bis-guanidiums bearing strong electron withdrawing substituents (PTC 26s to PTC 26u), the last steps should be carried out at 50 to 60 oC, since the structures of these bis-guanidiums were less stable to heat and only 20 to 30% overall yield could be achieved. Besides these successful examples, many designs of bis-guanidium structures were failed to be synthesized even with all our efforts. In most cases, the problem appeared at the last step that compound 48 could not couple with the linker due to the too much steric hindrance. Some examples are presented in Figure 1.5. 33 Chapter 1. The Syntheses of Various Bis-Guanidium Salts 48w 48x 48y 48z Figure 1.5. Imidazoline Salts of Highly Steric Hindrance which were failed to Couple with Piperizine. There are also failed attempts due to the electronic effects, and a selected example is shown in Scheme 1.23. After the first coupling, the aromatic ring system transported part of the positive charge to the other conjugate nitrogen atoms and reduced its nucleophilicity so that only monoalkylated product was obtained. Scheme 1.23. Monocoupling of Imidazoline Salt 48b with Linker 49 due to the Electronic Effect. 1.3 Summary Over the years, many types of asymmetric phase-transfer catalysts have been 34 Chapter 1. The Syntheses of Various Bis-Guanidium Salts synthesized and studied. Hugh success has been achieved by now but problems such as high catalyst loading and long synthetic route were still significant. Our group recently developed a new type of bis-guanidium salts as phase-transfer catalysts. More than 20 catalysts of this family have been synthesized in 4 to 5 steps from cheap, commercial available chiral sources with good overall yields. Synthetic procedures for highly sterically hindered and strong electron withdrawing bis-guanidiums are still needed to be further optimized. As an extension of this work, these chiral bis-guanidium salts were used for reactions, which will be discussed in the next chapter. References 1 (a) M. E.Halpern, Phase Transfer Catalysis, Mechanisms and Synthesis;American Chemical Society: Washington, DC, 1997; (b)Handbook of Phase Transfer Catalysis, Sasson, Y., Neumann, R.Eds.; Blackie: London, 1997; (c) C. M.Starks,C. L.Liotta,M. C. Halpern,Phase-Transfer Catalysis: Fundamentals,Applications, andIndustrial Perspectives; Chapman & Hall: New York, 1994; (d) PhaseTransfer Catalysis; E. V.Dehmlow,S. S.Dehmlow, VCH:Weinheim, Germany, 1993. 2 B. Lygo, Phase-Transfer Reactions. Rodd’s Chemistry of CarbonCompounds, Vol. V: Asymmetric Catalysis; Elsevier ScienceLtd.: Oxford, U.K. 2001, pp101–149. 3 R. A. Jones, Quaternary Ammonium Salts. Their Use in Phase-Transfer Catalysis; Academic Press: London, 2001. 4 (a)M. Makosza, Tetrahedron Lett.1966, 7, 4621–4624;(b)M. Makosza,Tetrahedron Lett.1966, 7, 5489–5492;(c)M. Makosza, Tetrahedron 35 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Lett.1969, 10, 673–676;(d)M. Makosza, Tetrahedron Lett.1969, 10, 677–678;(e)A. Brndstrum, Adv. Phys. Org. Chem. 1977, 15, 267–330. 5 C. M. Starks, J. Am. Chem. Soc.1971, 93, 195–199. 6 (a)M. Makosza, Pure Appl. Chem.1975, 43, 439–462; (b)H.-M. Yang,H.-S. Wu, Catal. Rev.2003, 45, 463–540. 7 B. Lygo, B. Andrews,Acc. Chem. Res.2004, 37, 518–525 8 T. Hiyama,T. Mishima, H. Sawada, H. Nozaki,J. Am. Chem. Soc.1975, 97, 1626–1627 9 S. Usui, L. A.Paquette, Tetrahedron Lett.1975, 40,3495 – 3496. 10 U. Dolling, P. Davis, E. Grabowski,J. Am. Chem. Soc.1984, 106, 446–447. 11 M. J. O'Donnell,W. D. Bennett, S. Wu,J.Am. Chem. Soc.1989,111.2353–2355. 12 (a) E. J. Corey, F. Xu, M. C. Noe,J. Am. Chem. Soc. 1997, 119, 12414–12415; (b) B. Lygo, P. G. Wainwright, Tetrahedron Lett.1997,38, 8595–8598. 13 (a) T. Ooi, M. Kameda, K. Maruoka.J.Am. Chem. Soc. 2003, 125, 5139–5151; (b) T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222 – 4266; (c) T. Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656–5682. 14 T. Kita, A. Georgieva, Y. Hashimoto, T. Nakata, K. Nagasawa. Angew. Chem. Int. Ed.2002, 41, 2832–2834. 15 N. Mase, T. Ohno, N. Hoshikawa, K. Ohishi, H. Morimoto, H.Yoda, K. Takabe, Tetrahedron Lett.2003, 44, 4073– 4075. 16 H. Sasai (Jpn. Kokai Tokkyo Koho), JP2003335780, 2003. 17 (a)T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine, T. Ohshima,M. Shibasaki,Tetrahedron Lett.2002, 43, 9539–9543; (b)T. Ohshima, T.Shibuguchi, 36 Chapter 1. The Syntheses of Various Bis-Guanidium Salts Y. Fukuta, M. Shibasaki, Tetrahedron,2004, 60, 7743–7754. 18 (a) W. E. Kowtoniuk, D. K. MacFarland, G. N. Grover, TetrahedronLett.2005, 46, 5703–5705;(b) M. E. Rueffer, L. K. Fort,D. K. MacFarland, Tetrahedron: Asymmetry, 2004, 15, 3297–3300. 19 D. J. Cram, G. D. Y. Sogah, J. Chem. Soc. Chem. Commun.1981, 625–628. 20 A. E. Sheshenev, E. V. Boltukhina, A. J. P. White, K. K. Hii, Angew. Chem. Int. Ed. 2013, 52, 6988 – 6991. 37 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Chapter 2 Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compounds Chapter 2: Bis-Guanidium Catalyzed Mukaiyama Type SN 2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Comp ounds 39 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound 2.1 Introduction of Asymmetric Organocatalysis of Chiral Quaternary Ammonium Fluorides 2.1.1 General Introduction Quaternary ammonium salts, which are known as one of the most important branches of phase-transfer catalysts, have different applications when bearing different counter ions. Compared with quaternary ammonium hydroxides, quaternary ammonium fluorides were less studied before, now have drawn many people’s attention, due to its specific affinity to silicon atom and relatively strong basicity in aportic solvents.1 The strong F-Si bond enables quaternary ammonium fluorides as a specific deprotecting reagent to silyl groups, which can generate nucleophiles from silicon protected compounds. The relatively strong basicity of fluoride anions in aprotic solvents allows direct deprotonation from substrates with lower pKa, and makes the fluoride anions an alternative to OH-. Both of these two properties make quaternary ammonium fluorides a great reagent or catalyst in organic syntheses, especially in asymmetric versions. Therefore, I reviewed most of the previous literatures in this area, and presented them below. 2.1.2 Previous Reports with Chiral Quaternary Ammonium Fluorides The first asymmetric example using chiral quaternary ammonium fluoride catalyst was a Michael addition reaction of nitromethane to chalcone done by Wynberg in 1978.2 In his procedure, the chiral catalyst 2 and 4a with fluoride anions were in situ generated by conteranion exchange of catalyst 1 and 3a (10 mol%) with excess amount of KF (15 equiv.) in toluene at 20 40 o C (Scheme 2.1). Although the Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound enantioselectivity for both of these two catalysts was not satisfying, comparison of the experimental data could be enlightening. Regardless the structure difference of cations, the catalyst with bromide as counter anion showed lower yield than the catalyst with chloride counter anion. So besides the enantioselectivity, the efficiency of counter anion exchange should also be taken into consideration. Scheme 2.1. Asymmetric Conjugate Addition of Nitromethane to Chalcone Catalyzed by In Situ Formed Chiral Quaternary Ammonium Fluorides. Maruoka did a systematic study on this problem using Mukaiyama aldol reaction as a model.3 The catalytic amount of fluoride anions were just the initiators to the reaction and the intermediate formed by nucleophilic addition of the enolate to benzaldehyde could further deprotect another molecule of silyl protected compound so that closed the catalytic cycle. Therefore, the counterion exchange basically only existed at the very beginning stage, and the whole process could hardly be regarded as phase-transfer catalysis for the mechanism we just mentioned above. 41 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.2. Counterion Effect of the Catalyst in Mukaiyama Aldol Reaction. From Scheme 2.2 we can see that, only when the counterion is HSO4-, the results could be comparable with those of directly using F- as the counterion. Some lipophilic anions even showed no catalytic effect. This phenomenon actually can be explained by different distribution rates of anions in a heterogeneous system (Table 2.1). Since the system is an organic/ solid heterogeneous system, anions with higher order of lipophilicitiy will be preferred in the exchange between catalysts in organic phase and solid salts. Table 2.1. Order of Lipophilicities of Anions. Although there are many factors in a reaction system may affect the selectivity of anions, the most important two factors are sizes and the number of charges of the 42 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound anions. Anions with larger ratio of volume/ N(charge), will be more lipophilic theoretically. It is easier to be understood that some anions (Br-, I-, etc.) might poison the catalyst. The equilibrium between these anions and fluoride anion far more prefers the former fat ones, so the functional quaternary ammonium fluorides just own very little percentage in organic layer that bad reaction yields were obtained. Interestingly, when the counterion was HSO4-, which is obviously more lipophilic than F-, and has similar lipophilicity to Cl-, the reaction showed great improvement on yield (up to 91% isolated yield). It’s because that the HSO4- can be deprotonated in the reaction system by F-, and eventually form SO42-, which is less lipophilic than F- so that no catalyst poisoning effect could be observed. After acquiring a better understanding of the reaction mechanism, Maruoka succeeded to develop its chiral version with his classical catalysts in 2001.3 During the optimization, they found that the mixed solvent of THF and toluene showed better diastereo- and enantioselectivities. Excellent yields and good to excellent enantiomeric excesses were obtained (Scheme 2.3). When optimizing the reaction, they found that the electron withdrawing Ar group was important since the chiral cation could form a tighter ion pair with fluoride anion and the following enolate generated from silyl enol ether. 43 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.3. Cyclic Type of Asymmetric Mukaiyama Aldol Reaction. Another example achieved by Maruoka using his catalysts with HSO4- as counterion is alkylative kenetic resolution of secondary alkyl halides.4 One example shown below is preparation of 1-(naphthalene-1-yl)ethyl 3-phenylpropanoate using 3-phenylpropionic acid and excess amount of 1-(1-bromoethyl)naphthalene, moderate enantiomeric excess was obtained (Scheme 2.4). Scheme 2.4. Alkylative Kenetic Resolution of Secondary Alkyl Halides. 44 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound But no synthetic route now can directly synthesize catalysts bearing HSO4- as counterion. Changing the counterion to F- sometimes can be more reasonable due to no extra fluoride source need to be added. Several counterion exchange methods were studied systematically by Shioiri and co-workers in 1993 to change the N-benzylcinchonium bromide 15a to its fluoride salt (Scheme 2.5).5 Following tests showed that the catalyst was stable under different methods of counterion exchange and the efficiencies of 15b prepared from different methods were the same (tested with Mukaiyama aldol reaction). Scheme 2.5. Methods of Counterion Exchange from Bromide to Fluoride. Furthermore, Shioiri did an asymmetric Mukaiyama aldol reaction with linear silyl enol ethers and benzaldehyde. Poor to moderate enantiomeric excesses were obtained using 15b and its peudoenantiomer 15c as catalysts (Scheme 2.6).5 45 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.6. Linear Type of Asymmetric Mukaiyama Aldol Reatcion. In 2001, Campagne and Bluet reported asymmetric vinylogous Mukaiyama aldol reaction catalyzed by 15b (Scheme 2.7).6 20% ee could be obtained at room temperature, and 30% ee at 0 oC. Scheme 2.7. Asymmetric Vinlogous Mukaiyama Aldol Reaction. In 1994, Iseki, Nagai, and Kobayashi reported asymmetric aldol reaction of aromatic aldehyde/ ketones and TMSCF3 initiated by fluoride anions. The catalysts 15d and 15e were prepared from corresponding bromides, and up to 51% ee was obtained (Scheme 2.8).7 46 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.8. Asymmetric Trifluoromethylation of Aromatic Aldehyde and Ketones. In 1997, Lawrence reported asymmetric reduction of aromatic ketones using polymethylhydrosiloxane (PMHS) and other silanes as hydride source. Although PMHS might accelerate the reaction rate significantly, the enantiomeric excess was only 28%. Less reactive (TMSO)3SiH could result in better enantioselectivity (65% ee) but longer reaction time (Scheme 2.9).8 Scheme 2.9. Asymmetric Reduction of Ketones with Alkoxysilanes. Since fluoride anion can form strong hydrogen bonds with protic compounds, in 47 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound nonpolar solvents R4N+F- generally exists as the adduct of hydrogen halides and water, R4N+F-(HY)n. This property can explain the hygroscopic nature of R4N+F-. However, under strictly anhydrous conditions, Hoffman elimination may happen due to intramolecular deprotonation of fluoride anion so that the ammonium salt will degrade to trialkylamine, olefin and ammonium bifluoride salt (Figure 2.1).1 The resulting ammonium bifluoride salt is more stable and easier to be handled than corresponding fluoride salt so that it can be an alternative to deprotection the silyl groups. Figure 2.1. Hoffman Elimination of Tetraalkylammonium Fluoride Salt. In 1999, Corey reported an asymmetric Mukaiyama aldol reaction of TMS protected Schiff base 26 and aldehydes catalyzed by cinchonidine derived bifluoride 15f. Products of different diastereoselectivity could be formed under different reaction pathways. Syn-28 was obtained as the major product. Good to excellent enantiomeric excesses were obtained under optimized reaction conditions (Scheme 2.10).9 48 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.10. Asymmetric Synthesis of α-Amino Acid via Mukaiyama Aldol Reaction. In 2003, Maruoka used his designer chiral spiro ammonium bifluoride as catalyst, and finished the asymmetric version of Mukaiyama type nitroaldol reaction (Scheme 2.11).10 During the optimization, they found that further increasing the steric effect of Ar groups on the catalyst from 11a (X=HF2) to 11b could result in great improvement of diastereo- and enantioselectivity. Anti-nitroaldols were obtained as major products with excellent ee values. 49 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.11. Asymmetric Mukaiyama Type Nitroaldol Reaction. When they extended the substrate scope from different substituted benzaldehydes to trans-cinnamaldehyde, 1,4-addition product syn-32 was the major product, rather than nitroaldol product (with a ratio of 8:2). Interestingly, when the chiral catalyst was replaced by achiral catalyst TBAF, the ratio of Michael and nitroaldol type product was 1.1: 1 which indicated the in situ formation of ammonium nitronate salts (Scheme 2.12). Furthermore, Muruoka studied this reaction thoroughly and developed a larger substrate scope for this Mukaiyama type Michael addition reaction.11 50 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.12. Asymmetric Michael Addition of TMS-Protected Nitroethane to Trans-Cinnamaldehyde. 2.1.3 Conclusion Asymmetric catalysis using ammonium fluoride salts as catalysts is still not fully developed now and it is lack of significant improvement recent years. Although Maruoka has done most of the pioneering works in this research area, the reactions mostly are limited to aldol and Michael addition reactions and enantioselectivity need to be further improved. Many other types of reactions have been solved using achiral ammonium fluorides as catalysts, so it is promising to develop their asymmetric versions. Also it is hopeful to improve the enantioselectivity by changing the chiral backbones of the catalysts and further tuning the reaction conditions. 51 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound 2.2 Brief Introduction of Asymmetric Organocatalysis of 1,4-Dicarbonyl Compounds 2.2.1 Brief Introduction 1,4-dicarbonyl compounds are kinds of very important and fundamental fragments in organic syntheses not only for its universal existence in organic compounds, but also for its easy introduction of further two chiral centers by reduction. There have been numerous protocols introducing the syntheses of these valuable substrates, but only a few of them can construct 1,4-dicarbonyl structures enantioselectivily. Most of these published examples can be categorized into three families: (1) Asymmetric reduction of dimethyl itaconate and its derivatives with H2 catalyzed by chiral transition metal complexes. (2) Asymmetric inter- and intramolecular Stetter reactions. (3) Enantioselective α-enolation of aldehydes via MacMillan’s SOMO catalysis. Transition metal (such as Rh2+, Rh+) catalyzed asymmetric hydrogenation of dimethyl itaconate and its derivatives have became a very successful method to synthesize chiral 1,4-diesters after several decades’ study. Both excellent yield and enantioselectivity can be achieved simultaneously. One of the latest examples Shown in Scheme 2.13 reported by Leitner in 2013 indicated that industrial application is the direction to further optimizing this reaction system.12 Continuous-flow process was applied in this work and supercritical CO2 was used as mobile phase. Full conversion and enantiopure product were achieved and turnover number of the catalyst was larger 52 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound than 100000 which mean at least 100 kg product could be produced with only 1 g of rhodium catalyst. Scheme 2.13.12 Concept of Asymmetric Hydrogenation of Dimethyl Itaconate with Flow Reactor. In 2013, Bouteiller also applied supramolecular catalyst to the hydrogenation of dimethyl itaconate and achieved excellent results.13 Since organometallic asymmetric catalysis is another branch of asymmetric catalysis and not extremely related to our topic asymmetric organocatalysis, further explanation won’t be included in this chapter. Stetter reaction was first discovered by Stetter in 1973 and consist of conjugate addition of acyl anion equivalents to α,β-unsaturated carbonyl compounds, which involved CN- or NHC carbenes as umpolung catalysts.14 The first example of asymmetric intramolecular Stetter reactions was reported by Enders in 1996 (Scheme 2.14).15 Although the enantiomeric excesses were just moderate, this pioneering work 53 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound inspired more groups to develop more efficient catalysts and suitable protocols and achieved excellent enantioselectivity. Scheme 2.14. First Asymmetric Intramolecular Stetter Reaction. The disadvantages of intramolecular Stetter reactions are quite obvious. One is extra steps to synthesize the starting materials and the other is only cyclic products could be obtained. Development of intermolecular Stetter reactions could solve these problems. Enders’ group reported the first asymmetric intermolecular Stetter reaction in 1993 with 4% yield and 39% ee.16 With continuous study on NHC catalysts, they found that the reactivity of the catalysts depended on the substituents on nitrogen greatly. So after 15 years, they reported the first successful example of asymmetric intermolecular Stetter reaction with moderate to good yields and good enantiomeric excesses (Scheme 2.15).17 They used the same catalyst and changed the Michael acceptors from substituted chalcones to arylidenemalonates and achieved moderate to good ees. 54 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.15. Selected Example of First Successful Asymmetric Intermolecular Stetter Reaction. Almost at the same time, Rovis independently published the asymmetric intermolecular Stetter reaction with good to excellent yields and enantioselectivities (Scheme 2.16).18 Scheme 2.16. First Asymmetric Intermolecular Stetter Reaction with Excellent Enantioselectivity. In 2011, Glorius reported the highly enantioselective intermolecular Stetter reaction of benzaldehyde derivatives to N-acylamido acrylate which produced enantioenriched α-amino acid derivatives (Scheme 2.17).19 55 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.17. Application of Asymmetric Intermolecular Stetter Reaction in the Synthesis of Enantioenriched α-Amino Acid Derivatives. In 2011, Gravel reported the first highly enantioselective intermolecular Stetter reactions on β-aryl substituted acceptors. Excellent results were obtained and a selected example is presented in Scheme 2.18.20 Scheme 2.18. Enantioselective Intermolecular Stetter Reactions on β-Aryl Substituted Acceptors. Still in 2011, Chi reported highly enantioselective Stetter type conjugate addition of enals to modified chalcones catalyzed by NHC catalysts and obtained excellent results (Scheme 2.19).21 56 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.19. Asymmetric Stetter type Michael addition of enals to modified chalcones. Bearing a similar idea to Stetter reactions, in 2006, Johnson reported metallophosphite catalyzed asymmetric acylation of α,β-unsaturated amides with excellent enantioselectivities (after recrystallization) and moderate to good yields.22 Besides asymmetric intra- and intermolecular Stetter reactions, MacMillan’s SOMO (singly occupied molecular orbital) catalysis is another mature and successful system to synthesize enantioenriched 1,4-dicarbonyl compounds. Mechanistically, the so-called SOMO catalysis is derived from enamine catalysis and further loses one electron via oxidation (Figure 2.2).23 57 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Figure 2.2. Concept of SOMO Catalysis. This in situ formed electrophile is then attacked by nucleophiles existing in the reaction system and generates the desired product. MacMillan has used this reaction system in many reactions and achieved great success including enantioselective construction of 1,4-dicarbonyl compounds (Scheme 2.20). R groups on the substrates could be aliphatic and aromatic groups. Scheme 2.20. Asymmetric SOMO Catalysis of 1,4-Dicarbonyl Compounds. In 2008, MacMillan reported the photocatalysis version of SOMO catalysis. The former oxidant CAN was replaced by fluorescent light and photoredox catalysts (Scheme 2.21).24 When 56 was α-bromocarbonyl compound, the product was 1,4-dicarbonyl compound. Scheme 2.21. Photocatalysis Version of SOMO catalysis. 58 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound There are some other publications of construction of 1,4-dicarbonyl compounds that cannot be categorized into these three catalytic families. For example, in 2010, Feng reported highly enantioselective aza-ene type reaction catalyzed by chiral N,N’-dioxide-nickel(II) complex (Scheme 2.22), and excellent results were obtained.25 Scheme 2.22. Enantioselective Aza-Ene Type Reaction Catalyzed by Chiral N,N’-Dioxide-Nickel(II) Complex. 2.2.2 Conclusion Enantioenriched 1,4-dicarbonyl compounds are kinds of very important and fundamental fragments in organic syntheses, and the synthesis of them is still an underdeveloped field. Oganocatalysis systems have been applied and achieved great success. Both of NHC catalysts and MacMillan’s proline type catalysts can form covalent bonds with starting materials so that the further chiral induction is easy and robust. To my best knowledge, there is no example using phase-transfer catalysis system to synthesize enantioenriched 1,4-dicarbonyl mechanistically should be possible and convenient. 59 compounds, which Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound 2.3 Fluoride Anions Mediated Enantioselective Mukaiyama Type SN2 Alkylation Reaction Catalyzed by Bis-Guanidium Salts. 2.3.1 Trigger of the Project In 2009, our group reported a highly enantioselective conjugate addition reaction of 1,4-dicarbonyl but-2-enes to synthesize α-Stereogenic Amides and Ketones (Scheme 2.23). Both excellent yields and ees could be obtained using our classic guanidine catalyst.26 Scheme 2.23. Enantioselective Conjugate Addition Reaction of 1,4-Dicarbonyl But-2-Enes to Synthesize α-Stereogenic Amides and Ketones. Although the results were perfect, the disadvantages were also obvious. The substrates were not easy to synthesize since more than one electron withdrawing groups were needed to lower the pKa of the starting materials. Some unusual auxiliaries were added to achieve high ees due to the difficulties in modifying the catalyst. All these years, we have been seeking a method to solve these problems until we 60 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound started to study phase-transfer catalysis system and invented our easily modified phase-transfer catalysts introduced in Chapter 1. Catalytic properties of phase-transfer catalysts are heavily depended on the counter ions so that the basicity is tunable by changing the inorganic bases. Also many fragments of the catalysts can be easily modified to obtain appropriate steric and electronic effects so that extra auxiliary is not necessary to high enantioselectivity. Using retrosynthetic analysis, 1,4-dicarbonyl compounds can be easily obtained from propiophenone type substrates by reacting with α-bromoesters under basic conditions, and it is possible to achieve high enantioseletivity with a huge catalyst library in hand. At that moment, the basic idea of this project started to become clear. 2.3.2 Guanidium Salts Catalyzed Asymmetric SN2 Alkylation Reaction To prove the concept, propiophenone and methyl bromoacetate were the most straightforward choices to be the starting materials, and were tried in toluene-50% NaOH (aq.) bi-layer system. No desired product was obtained due to fast decomposition of methyl bromoacetate under strong basic condition. (Z)-1-phenylprop-1-en-1-yl acetate was also prepared and tried in this reaction which could generate enolates under weaker basic condition (10% NaOH aqueous solution). However unfortunately, this level of basicity was still too high to methyl bromoacetate (Scheme 2.24). Further studies showed that 66 could decompose even using Cs2CO3 solid as the base, which indicated that Brønsted base might not be suitable to this alkylation system. 61 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.24. Failed Attempts of OH- Mediated Alkylation Reactions. Silyl enol ethers have been used as enolate precursors for more than half a century, and the specific affinity of fluoride anions to silicon can ensure the deprotection of silyl groups and tolerance of other sensitive parts at the same time. Pioneering works done by Maruoka in asymmetric Mukaiyama aldol reactions showed the possibility to solve our problem with chiral ammonium fluoride salts. Model reaction was carried out using TMS protected propiophenone derived silyl enol ether and methyl bromoacetate as starting materials and stoichiometric amount of CsF solid as fluoride source (Scheme 2.25). The reaction couldn’t finish in 5 days at room temperature and the yield was 52% when a lot of silyl enol ether still remained. The only significant byproduct was propiophenone formed by protonation of generated enolate. It was difficult to track back the proton source (compound 66 or water), since the reaction yield was extremely low when the system was critically unhydrous. 62 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.25. Model Reaction of Mukaiyama Type SN2 Alkylation Reaction. With the racemic condition in hand, we started to screen the chiral PTCs in our library and some commercial available cinchonidine derived PTCs. The results of first round of catalyst screening are shown in Table 2.2. Since it’s the preliminary screening of the catalysts, isolated yields were just calculated for the promising entries. Full catalyst list is presented in Table 2. 13 at the end of Section 2.3.2. Table 2.2. First Round of Catalyst Screening Results of the Model Reaction. Entrya Catalyst Solvent Temperature (oC) Ee (%)b 1 PTC 1 TBME 0 25 (40% yield)c 2 PTC 2 TBME 25 10 3 PTC 3 TBME 25 7 4 PTC 4 TBME 25 15 5 PTC 5 TBME 25 5 6 PTC 6 TBME 25 12 7 PTC 7 TBME 25 5 8 PTC 8 TBME 25 0 9 PTC 9 TBME 25 n.p. 10 PTC 10 TBME 0 5 11 PTC 11 TBME 25 n.p. 12 PTC 12 Toluene 0 7 13 PTC 13 Toluene 0 0 63 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound a 14 PTC 14 Toluene 0 5 15 PTC 15 Toluene 0 6 16 PTC 16a TBME 0 30 (50% yield) c 17 PTC 16a Toluene 0 50 (55% yield) c 18 PTC 16b TBME 0 7 Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents. b Determined by HPLC analysis. c Isolated yields. During this round of catalyst screening, we tried all the pentanidiums in our catalyst library. Previously published full methylated pentanidium PTC 1 showed 25% ee (optimized) and 40% yield in 24 hours. Any other pentanidium derivatives with larger steric effects and different distribution of the chiral centers showed lower enantioselectivity and activities of catalysis (Entry 2 to 8). No desired product was obtained when electron withdrawing R groups were attached to nitrogen (Entry 9). At this point, it was clear that the scaffold of pentanidium salts was not suitable in this reaction system. Three commercial available cinchonidine derived PTCs were tried in the model reaction. The reaction rates were faster than those of pentanidiums, but basically no reliable enantiomeric excess was obtained (Entry 13 to 15). PTC 11 which had been proven to be effective in fluoride anion mediated Mukaiyama aldol reactions showed no catalytic activity in this SN2 alkylation reaction. However, highly sterically hindered bis-guanidium salt PTC 16a showed great match with the substrates. 50% ee was obtained when toluene was used as solvent, and the reaction rate was greatly higher than those of PTC 1. While full methylated bis-guanidium salt PTC 16b provided bad results, implying that the steric effect was 64 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound important in this case. Further studies proven that the bis-ammonium scaffold was necessary to the enantioselective control, since enantiomeric excesses of the mono-guanidium salts were not higher than 10% (Entry 10 and 12). With an appropriate catalyst in hand, we began to optimize the reaction condition. Firstly, we screened solvents and inorganic fluoride salts (Table 2.3). The isolated yields were only calculated for promising entries. Table 2.3. Preliminary Screening of Solvents and Fluoride salts. Entrya Solvent F- source Temperature (oC) Conv. (%)b 1 Toluene CsF 0 90 (55) d 50 2 Cyclohexane CsF 0 50 27 3 Mesitylene CsF 0 20 36 4 o-Xylene CsF 0 80 42 5 m-Xylene CsF 0 80 42 6 4-t-Bu-toluene CsF 0 90 (70) d 55 7 Ethylbenzene CsF 0 90 48 8 Anisole CsF 0 100 31 9 DCM CsF 0 100 0 10 TBME CsF 0 90 30 11 4-t-Bu-toluene CsF -20 trace n.d. 12 e Toluene AgF 0 100(30) d 56 13 e m-Xylene AgF 0 100(38) d 68 65 Ee (%)c Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound a 14 e o-Xylene AgF 0 100 63 15 e 4-t-Bu-toluene AgF 0 100(50) d 71 16 Mesitylene AgF 0 trace 67 17 e TBME AgF 0 100 40 18 e DCM AgF 0 100 0 19 e Cyclohexane AgF 0 100 45 20 e Trifluorotoluene AgF 0 100 18 21 Toluene AgF -20 trace 48 22 Toluene AgF 25 100 (30) d 46 Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Conversion was based on 68a determined by TLC.c Determined by HPLC analysis. d Isolated yields. e The reaction could be finished in 8 hours. From the data presented in Table 2.3 we could see that toluene type solvents were more preferable than DCM, ether type and alkane type solvents no matter the fluoride salt was CsF or AgF. Further screening was carried out among toluene type solvents. Ethylbenzene showed little difference with toluene on aspects of ee and yield. O-xylene and m-xylene were tested which provided higher enantiomeric excesses than toluene when AgF was applied (Entry 13 and 14). P-xylene was not taken into consideration due to its higher melting point than 0 oC. Highly steric hindered mesitylene showed bad conversions under reaction conditions (Entry 3 and 16). More polar derivatives showed better reaction yield but far lower ees (Entry 8 and 20). AgF showed better enantioselectivity and faster speed of starting material consumption than CsF, but lower yields due to strong side reactions induced by Ag+ (dehalogenation and other effects). More propiophenone was produced and the spots 66 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound on TLC plates were messy. The situation could be improved by using 4-t-Bu-toluene as solvent, but the yield was still not satisfying. Dramatically, both CsF and AgF showed no activity when the temperature went down to -20 oC, although at 0 oC the reactions were still robust. It should be an important phenomenon, but we couldn’t find a reasonable explanation. Silver fluoride salts of different purity levels (99% and ≤ 99.9% purchased from Sigma-Aldrich) were tested, and no obvious difference was observed. Different ratios of the two substrates (2:1, 1:1, 1:2) and the concentrations (0.06 M, 0.13 M, 0.25 M) for promising entries were also tested at this moment (not shown in the tables), yields and reaction rates could be affected, but enantioselectivity showed no obvious difference. At this preliminary stage, the best result was 71% ee and 50% isolated yield (Entry 15) temporarily, and further optimization was still needed. Later more commercial available inorganic fluoride salts were screened, Namely NaF, KF, RbF, KHF2, MgF2, CaF2, SrF2, BaF2, NH4F, Na3AlF6, GaF3, NH4HF2, TiF3, VF3, MnF2, FeF2, FeF3, CoF2, NiF2, CuF2, ZnF2, AgF2, SnF4. However, none of them could activate the silyl compounds under standard condition. Hg2F2 was the most possible alternative to AgF since Hg+ has similar properties to Ag+. However its importation was forbidden by Singapore government so that we didn’t obtain this data. During the optimization, an interesting phenomenon came to us (Table 2.4). When the 1:1 mixtures of AgF and wet CsF (stored in open air) were used as fluoride source, 78% ee was obtained with lower reaction rate (Entry 3). The yield was not determined, since it depended on the amount of water contained by CsF. However, when we used dry CsF (freshly taken out of glovebox) and mixed it with AgF, both ee and yield were just the same as those of CsF (Entry 4). 67 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Table 2.4. Screening of Fluoride Salts with the Model Reaction. a Entrya F- source yield (%) ee (%)b 1 CsF 70 50 2 AgF 50 71 3 AgF: CsF(wet)= 1:1 n.d. 78 4 AgF: CsF(dry)= 1:1 72 52 Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Determined by HPLC analysis. From the data presented in Table 2.4, we proposed that the preferred fluoride source in the reaction system should be CsF due to the similar results of Entry 1 and 4. It could also be supported by HSAB theory (hard and soft acids and bases theory) and dehalogenation effect of silver cation, in which case Ag+ is soft, F- is hard, and Cs+ is in between so that AgF prefers to exchange its anion with CsBr and precipitates out as AgBr. The existence of trace amount of free water may also help to dissolve the inorganic salts and accelerate the anion exchange. However due to some unknown reasons, stoichiometric amount of CsF is not good to achieve high enantiomeric excess so that a better way is to in situ generate CsF which means there will be only catalytic amount of CsF existing in the system throughout the reaction. The fluoride anions of wet CsF are fully bonded and deactivated by H2O molecules so that the 68 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound anion exchange with AgF may generate catalytic amount of “active” CsF and further results in higher ee value of Entry 3. To prove the existence of anion exchange in solid phase, we used CsF as fluoride source and added different sodium salts (whose anions cannot form strong competition with F-) in to the system. Since NaF cannot activate the silyl compound under standard condition, if the exchange can really happen, there should be trace amount of product or even no product (Scheme 2.26). As we predicted, no reaction happened when 1 equivalent sodium salts were added so that our proposed mechanism was reasonable. Scheme 2.26. Proof of Anion Exchange in Solid Phase. Then the most urgent thing we need to do was to find a suitable Cesium salt bearing a soft anion so that the anion exchange could happen with an appropriate rate. Several commercial available Cesium salts were tested and the results were presented in Table 2.5. Table 2.5. Screening of Different Cesium Salts as Additives in the Model Reaction. 69 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound a Entrya Additives Yield (%) Ee (%)b 1 CsCl 65 79 2 CsOH∙xH2O trace n.d. 3 Cs2CO3 30 74 4 CsNO3 58 56 5 (COOCs)2 67 75 6 CsOAc 69 84 7 HCOOCs 71 84 8c AgOAc 52 50 9c NaOAc n.r. -- Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Determined by HPLC analysis. c No cesium salt was added. From the data in Table 2.5 we could see that cesium acetate and cesium formate provided the best results that increased enantiomeric excesses to 84% with roughly 70% yield (Entry 6 and 7). Changing cesium acetate to silver acetate showed no improvement on ee indicating that the enhancement of ee was not induced by addition of acetate anions (Entry 8). Data of Entry 9 could be explained by our proposed anion exchange mechanism. Since sodium fluoride couldn’t mediate the reaction, no reaction happened when we changed cesium acetate to sodium acetate. Different ratios of AgF and CsOAc were tested and the results were presented in Table 2.6. 70 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Table 2.6. Testing of Different Loadings of CsOAc in the Model Reaction. a Entrya Equiv. of CsOAc Yield (%)b Ee (%)c 1 1 69 84 2 2 54 83 3 0.5 68 83 4 0.1 55 69 Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Isolated yields.c Determined by HPLC analysis. During the optimization, we found that when the loading of CsOAc was between 0.5 equivalents to 2 equivalents, the ee was independent to CsOAc. But more CsOAc was added, slower the reaction became due to the anion competition of F- and OAc- so that we didn’t try loadings higher than 2 equivalents. When only 10 mol% CsOAc was added, the result was much similar to that of AgF alone. We also succeed to lower the loading of AgF to 1 equivalent since silver was expensive and heavy metal, and no difference in yield and ee was observed. But in the following optimization, we still used 2 equivalents of AgF due to easy weighing with balance. With this mature reaction condition in hand, we started to tune the structure of bis-guanidium catalyst, and the data of this round of tuning is presented in Table 2.7. Full catalyst list is presented in Table 2. 13 at the end of Section 2.3.2. 71 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Table 2.7. Catalyst Screening of Bis-Guanidium Salts with the Model Reaction. Entrya Catalyst Conv. (%)b Ee (%)c 1 PTC 16a 90 86 2 PTC 16b 80 9 3 PTC 16c 80 0 4 PTC 16d 90 0 5 PTC 16e 80 3 6 PTC 16f 80 -10 7 PTC 16g n.p. -- 8 PTC 16h 90 -13 9 PTC 16i 90 20 10 PTC 16j 80 17 11 PTC 16k 60 20 12 PTC 16l n.p. -- 13 PTC 16m 90 74 14 PTC 16n 80 12 15 PTC 16o 30 34 16 PTC 16p 80 48 17 PTC 16q n.p. -- 18 PTC 16r 60 33 19 PTC 16s 90 30 20 PTC 16t 90 15 72 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound a Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Conversion was based on 68a determined by TLC. c Determined by HPLC analysis. Before the screening, honestly we were quite optimistic that this round of catalyst screening could push the ee value to 90%, since we had only tried two bis-guanidium salts, and there were still a lot of positions on the catalyst scaffold could be modified. But the results were not as good as our prediction. The model catalyst PTC 16a showed the best ee among the 20 bis-guanidiums we screened. R groups on nitrogen were the easiest place to modify. From the data we could see that, 3,5-disubstitutions on phenyl rings of the R groups were very important for enantioselectivity. The only one catalyst that showed comparable ee value with PTC 16a was PTC 16m, whose R groups on nitrogen were 3,5-di(TMS)-benzyl groups. Extra substituent on position 2 of the phenyl ring provided low ee (Entry 6 and 14). Strong electron withdrawing or strong electron donating groups substituted bis-guanidiums couldn’t catalyze the reaction under the standard condition (Entry 7 and 12). Further modification was made on chiral backbones. Phenyl rings attached to the chiral centers were modified with steric (para-methyl phenyl, para- t-butyl phenyl, β-naphthyl phenyl groups), electron withdrawing (para-trifluoromethyl phenyl groups) and electron donating groups (para-methoxyl phenyl groups). But none of them showed acceptable result regarding to ee value. The third and the last type modification we could think of was done on the central linker. Beside piperazine, we also tried 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Entry 20), N1,N2-dimethylethane-1,2-diamine 73 (Entry 4) and Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound (2S,5R)-2,5-dimethylpiperazine (Entry 11) as the linker, but still the ee dropped dramatically. With a series of setback in catalyst modification, we turned our focus to the tuning of two starting materials. Theoretically, we would only tune the protecting groups, leaving groups and ester groups which wouldn’t narrow down the substrate scope and keep the methodology universal. Firstly, we tried TES and TBS groups to replace TMS group. The new silyl protected enolate precursors were more stable than original TMS protected starting material, and could be isolated by silica column. But when we used them in the model reaction, no reaction happened in 24 hours and all silyl compounds were recovered. Further tuning of silyl groups would be meaningless, since TES was the most sensitive silyl group to fluoride anions except for TMS group. So using the mixture of AgF and CsOAc as the fluoride source, the only available silyl protecting group was TMS group. As to the ester part, actually there are lots of strategies could be used. Scheme 2.27 showed different modifications we had tried and their results. 74 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.27. Results of Modification on Ester Part for the Model Reaction. Results showed that simple extension of aliphatic chain was not useful to improve ee value. While bulky groups and electron withdrawing groups might result in side reaction and no desired product could be obtained. Changing the ester to thioester showed no desired product due to the great changing of electronic effect. We could isolate desired product by using α-bromoamide to replace α-bromoester, but the yield was too low so that we gave it up. An interesting phenomenon was, although bulky α-bromoester couldn’t provide desired product when AgF was contained in the reaction system, it could be used when we simply applied CsF as the fluoride source which indicated that AgF (and the mixture of AgF and CsOAc) might undergo a different pathway compared with CsF. Further optimization was carried out on the leaving groups shown in Scheme 2.28. We firstly changed the bromide to other halides, only Chloride showed trace amount of product. And once again, the α-iodoester which was not applicable to the mixture of AgF and CsOAc, could be used under the condition that using CsF as fluoride 75 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound source which could be explained by the dehalogenation effect of silver cation. When we changed the bromide to some softer leaving groups, such as NO3 and OTs groups, no desired product was formed. Scheme 2.28. Effects of the Leaving Groups on the Model Reaction. During the optimization, we accidentally found that if we mixed trace amount of bulky alcohols in the solvent, the ee values could be improved slightly, but too much alcohols could quench the reaction. Further tuning showed that mixing 5 mol% TMSOH into the solvent showed 86% ee (2% ee increased) under standard condition (Scheme 2.29). Scheme 2.29. Finalized Reaction Condition to the Model Reaction Using Mixture of AgF and CsOAc as Fluoride Source. After the optimization, we prepared several different substituted silyl enol ethers and 76 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound used them under optimized condition (Table 2.8). The substrate scope was not so satisfying that all other substrates tested showed lower ee than the model 68a. Entry 2 showed lower yield, since the electron donating group could stabilize its silyl groups. Chloride on phenyl ring could significantly accelerate the reaction, but meta substituted substrate showed lower ee. The cyclic example, which was applicable when CsF was used as fluoride source, showed no desired product when the fluoride source was the mixture of AgF and CsOAc. More substrates could be synthesized, but due to the limited time, broader substrate scope wasn’t done. Table 2.8. Substrate Scope Using Mixture of AgF and CsOAc as Fluoride Source. Entrya yield (%)b Ee (%)c 1 70 86 2 40 70 3 75 81 4 72 67 Silyl enol ethers 77 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound 5 a n.p. -- Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 150 μL solvents, dark.b Isolated yields. c Determined by HPLC analysis. During the optimization, we accidentally found that weak acidic condition was important to enantioselectivity, but too much acid might quench the reaction. Compound 66 could slowly decompose in a hot circumstance and generate HBr so that sometimes 66 with slightly decomposition showed max. 10% ee higher than normal 66. However, we failed to catch this narrow pH window. Although the application of AgF could provide the highest ee, lots of unsolved problems were induced by it. Firstly many substrates couldn’t be used in AgF system. Secondly, the mechanism was complicated and many other effects were involved into the system which made the optimization lack of direction and the repeatability of reaction was poor. Thirdly, silver fluoride was much more expensive and toxic than other fluoride salts. For the reasons presented above, we decided to try some new fluoride sources. The reagent attracted us was tetramethyl ammonium fluoride, which is short for TMAF. It can also be a phase-transfer catalyst in polar solvents. But in non-polar solvents, the catalytic ability is depressed due to its bad solubility and strong hydrophilicity. So it is possible to obtain enantiomeric excess if we use catalytic amount of chiral PTC and stoichiometric amount of TMAF in the system (Table 2.9). Table 2.9. Optimization Using TMAF as Fluoride Source. 78 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound a Entrya Equiv. of TMAF Solvent Temp.(oC) Conversion (%)b Ee (%)c 1 2 Toluene -30 100 30 2 2 Toluene -60 80 48 3 1 Toluene -60 70 58 4 1 Toluene -80 70 60 5 1 TBME -60 n.p. -- 6 1 Ether -60 90 35 7 1 4-t-Bu-toluene -60 80 40 8 1 DCM -80 100 0 9 1 n-Hexane -60 40 18 Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 300 μL solvents. b Conversion was based on 68a determined by TLC. c Determined by HPLC analysis. We firstly set up the reaction at -30 oC in toluene with 2 equivalents of TMAF. The reaction was so fast that 100% conversion was achieved in 3 hours. Lowering the temperature to -60 oC could increase the ee value by 18% and the reaction could be finished in 24 hours. No propiophenone was formed at such a low temperature and all consumed starting material 68a was turned into the desired product. Further decrease of the temperature showed very little increase on ee. Blank reaction (without chiral PTC) under this condition showed strong background reaction so that we decided to reduce the loading of TMAF to 1 equivalent, and further 10% increased ee value was obtained. 79 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Full screening of solvents showed that toluene was the best solvent in this modified system. Concentration of the solution could affect the ee value this time, and 0.07 M (based on 68a) was the optimized concentration after several careful tests. With this stronger fluoride salt in hand, we went back to the test of other silyl groups. TBS and TES were tested, and at -30 oC, the results of these two protecting groups were better than that of TMS. But the ee values didn’t response to temperature decrease so that at -60 oC, TBS and TES showed lower ee than TMS (Table 2.10). Table 2.10. Effects of Different Silyl Protecting Groups on the Model Reaction. Entrya a Temp. (oC) Conv. (%)b Ee (%)c 1 -30 100 50 2 -30 100 49 3 -80 50 50 4 -80 50 50 Silyl compounds Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 300 μL solvents. b Conversion was based on 68a determined by TLC. c Determined by HPLC analysis. Based on this preliminary result, systematic optimization was carried out. Most of the data obeyed the trends obtained from AgF system. When we tested α-bromo 80 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound t-butylacetate, the ee value was increased by 10%, but the reaction was quite slow at -60 oC (Scheme 2.30). Scheme 2.30. Bis-Guanidium catalyzed Asymmetric Mukaiyama SN2 Alkylation Reaction with α-Bromo t-Butylacetate. Further tuning on catalyst showed that PTC 16o showed higher ee than original PTC 16a on model reaction (TMAF system). But the reaction rate was so slow that in 24 hours, only 20% to 30% 68a was consumed due to the higher activation energy of PTC+F- induced by electron withdrawing substituents. So we decided to add some electron donating substituents on R groups to balance the charge distribution so that PTC 16u was synthesized and showed higher ee and yield than PTC 16o (Scheme 2.31). 81 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Scheme 2.31. Improvement on Ee Values by Tuning the Catalysts. Since the reaction rate for PTC 16u was still quite low, it need to be further optimized before it was applied to α-Bromo t-Butylacetate. Another direction of optimization was to decrease the loading of TMAF to catalytic amount, which meaned that TMAF should be able to regenerate between the interface of organic layer and solid and another stoichiometric fluoride salt would be needed (Figure 2.3). So the two catalysts form a relay in the system. This part of optimization was not totally finished, but preliminary result was obtained. Figure 2.3. Proposed two catalysts relay system. 82 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Under the standard condition, this relay couldn’t happen or was extremely slow, so two ideas were raised up to accelerate the anion exchange. One is to use mixed solvents, 90% non-polar solvent with 10% polar solvent, to increase the solubility of stoichiometric amount of inorganic fluoride salts, such as CsF and AgF so that accelerated the anion exchange between tetramethyl ammonium bromide (TMAB) and these inorganic salts. Background reaction could be minimized by lowering the temperature. The other idea was to use stoichiometric amount of ligand to coordinate with AgF and weaken the ionic bond between silver cation and fluoride anion so that the exchange between TMAB and AgF could be easier. Results of these attempts were presented in Table 2.11 and Table 2.12. From the data we could see that both of the idea was possible, but generally low yield was still a problem. Further investigation was needed in this area. Table 2.11. Effect of Mixed Solvents on the Model Reaction. a Entrya Additives Conv. (%)b Ee (%)c 1 THF 20 64 2 DCM 30 65 3 MeOH n.r. -- 4 None n.r. -- Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 300 μL solvents (9:1). b Conversion was based on 68a determined by TLC. c Determined by HPLC analysis. 83 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Table 2.12. Effects of AgF with Different Ligands on the Model Reaction. Entrya Ligand Conv. (%)b Ee (%)c 1 PPh3 30 20 30 48 30 66 n.r. -- 2 3 NEt3 4 a 5 Pyridine n.r. -- 6 DMAP n.r. -- 7 None n.r. -- Reactions were carried out on a 0.02 mmol scale with 5 mol% PTC in 1.5 mL sealed vials with 300 μL solvents. b Conversion was based on 68a determined by TLC. c Determined by HPLC analysis. Table 2.13. Full List of Catalysts Used in Chapter 2. Entry Structure Entry Code：PTC 1 MW.a: 550.14 Code：PTC 2 MW. a:926.75 84 Structure Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Code：PTC 3 MW. a: 1078.95 Code：PTC 4 MW. a: 1303.37 Code：PTC 5 MW. a: 954.81 Code：PTC 6 MW. a: 1151.18 Code：PTC 7 MW. a: 774.56 Code：PTC 8 MW. a: 610.19 Code：PTC 9 MW. a: 1398.50 Code：PTC 10 MW. a: 732.52 Code：PTC 11 MW. a: 351.27 Code：PTC 12 MW. a: 795.58 85 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Code：PTC 13 MW. a: 533.42 Code：PTC 14 MW. a: 605.61 Code：PTC 15 MW. a: 521.09 Code：PTC 16a MW. a: 1408.94 Code：PTC 16b MW. a: 655.70 Code：PTC 16c MW. a: 1160.32 Code：PTC 16d MW. a: 962.10 Code：PTC 16e MW. a:1160.32 Code：PTC 16f MW. a: 1724.52 Code：PTC 16g MW. a: 1320.40 Code：PTC 16h MW. a: 1184.51 Code：PTC 16i MW. a: 1240.62 Code：PTC 16j MW. a: 1529.04 Code：PTC 16k MW. a: 1436.99 86 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound Code：PTC 16m MW. a: 1537.54 Code：PTC 16n MW. a: 1546.72 Code：PTC 16o MW. a: 1680.93 Code：PTC 16p MW. a: 1609.17 Code：PTC 16q MW. a: 1588.93 Code：PTC 16r MW. a: 1633.36 Code：PTC 16s MW. a: 1465.04 Code：PTC 16t MW. a: 1432.96 Code：PTC 16u MW. a: 1801.03 a Code：PTC 16l MW. a: 1504.07 The molecular weights presented in the table were calculated by BioChemDraw Ultra 12.0. 2.3.3 Conclusion Asymmetric fluoride anion mediated phase-transfer catalysis was first used to synthesize 1,4-dicarbonyl compounds via Mukaiyama SN2 alkylation reactions. With our original chiral bis-guanidium catalysts, up to 86% ee and 70% yield were achieved. Meanwhile, fundamental problems about fluoride salts and phase-transfer catalysis were studied and discussed in the contents. Two catalytic systems were studied and further optimization is possible and necessary. 87 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound References 1 T. Ooi, K. Maruoka, Acc.Chem.Res.2004, 37, 526-533. 2 S. Colonna, H. Hiemstra, H. Wynberg, J. Chem. Soc., Chem. Commun. 1978, 238-239. 3 T. Ooi, K. Doda, K. Maruoka, Org. lett.2001, 3, 1273-1276. 4 T. Ooi, H. Sugimoto, K. Doda, K. Maruoka, Tetrahedron Lett. 2001, 42, 9245-9248. 5 A. Ando, T. Miura, T. Tatematsu, T. Shioiri, Tetrahedron Lett. 1993, 34, 1507-1510. 6 G. Bluet, J. M. Campagne, J.Org.Chem.2001, 66, 4293-4298. 7 K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron Lett. 1994, 35, 3137-3138. 8 M. D. Drew, N. J. Lawrence, W. Watson, S. A. Bowles, Tetrahedron Lett. 1997, 38, 5857-5860. 9 M. Horikawa, J. Busch-Petersen, E. J. Corey, Tetrahedron Lett. 1999, 40, 3843-3846. 10 T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 2054-2055. 11 T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 9022-9023. 12 U. Hintermair, G. Francio, W. Leitner, Chem. Eur. J. 2013, 19, 4538-4547. 13 M. Raynal, F. Portier, P. W. van Leeuwen, L. Bouteiller, J. Am. Chem. Soc. 2013, 135, 17687-17690. 14 H. Stetter, M. Schreckenberg, Angew. Chem. Int. Ed.1973, 12, 81. 15 D. Enders, K. Breuer, J. Runsink, J. H. Teles, Helv. Chem. Acta 1996, 79, 1899-1902. 88 Chapter2. Bis-Guanidium Catalyzed Mukaiyama Type SN2 Alkylation Reactions to Synthesize 1,4-Dicarbonyl Compound 16 D. Enders, T. Balensiefer, Acc. Chem. Res. 2004, 37, 534-541. 17 D. Enders, J. Han, A. Henseler, Chem. Commun.2008, 3989-3991. 18 Q. Liu, S. Perreault, T. Rovis, J. Am. Chem. Soc. 2008, 130, 14066-14067. 19 T. Jousseaume, N. E. Wurz, F. Glorius, Angew. Chem. Int. Ed.2011, 50, 1410-1414. 20 E. Sanchez-Larios, K. Thai, F. Bilodeau, M. Gravel, Org. lett. 2011, 13, 4942-4945. 21 X. Fang, X. Chen, H. Lv, Y. R. Chi, Angew. Chem. Int. Ed.2011, 50, 11782-11785. 22 M. R. Nahm, J. R. Potnick, P. S. White, J. S. Johnson, J. Am. Chem. Soc. 2006, 128, 2751-2756. 23 H. Y. Jang, J. B. Hong, D. W. MacMillan, J. Am. Chem. Soc. 2007, 129, 7004-7005. 24 D. A. Nicewicz, D. W. MacMillan, Science 2008, 322, 77-80. 25 K. Zheng, X. Liu, J. Zhao, Y. Yang, L. Lin, X. Feng, Chem. Commun.2010, 46, 3771-3773. 26 Z. Jiang, Y. Yang, Y. Pan, Y. Zhao, H. Liu, C. H. Tan, Chem. Eur. J.2009, 15, 4925-4930. 89 Chapter3. The Experimental Procedures Chapter 3 The Experimental Procedures Chapter 3: The Experimental Procedures 91 Chapter3. The Experimental Procedures 3.1 General Information 1 H and 13 C NMR spectra were recorded on a Bruker ACF300 (300MHz), Bruker DPX300 (300MHz), 500 MHz Bruker DRX NMR spectrometer or AMX500 (500MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Enantiomeric excess values were determined by chiral HPLC analysis on SHIMADZU HPLC units, including a DGU-20A5 Prominence Degasser, LC-20A7 Prominence Liquid Chromatograph and SPD-M20A Prominence Diode Array Detector. Flash chromatography separations were performed on Merck 60 (0.040 - 0.063 mm) mesh silica gel. Toluene was distilled from sodium/benzophenone and stored under N2 atmosphere. MeCN was dried by CaH2. Dichloromethane was distilled from CaH2. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. Reactions requiring temperatures 0 oC, -20 oC, -30 oC, -40 oC, -60 o C and -80 o C were stirred in Zhengzhou Great Wall DHJF-8002 Low-Temperature Stirring Reaction Bath. Isopropanol was used as the bath medium. All experiments were monitored by analytical thin layer chromatography (TLC). Instrumentations Proton nuclear magnetic resonance (1H NMR), carbon NMR (13C NMR) were recorded in CDCl3 otherwise stated. 1H (500.1331 MHz), 13C (125.7710 MHz) with complete proton decoupling, All compounds synthesized were stored in a -78 oC freezer. All silyl protected compounds were synthesized according to published procedures. Chiral diamines were purchased from Chengdu Likai Inc. and 92 Chapter3. The Experimental Procedures Diaminopharm Inc.. Synthetic procedures for commercial unavailable chiral diamines were based on (J. Am. Chem. Soc. 130, 12184). All other purchased chemicals and reagents were of analytical grade, obtained from Sigma Aldrich, TCI or Alfa Acesar and used without further purification unless specified. 3.2 Syntheses and Characterizations of Chiral Bis-Guanidium Salts Representative procedure for the synthesis of chiral bis-guanidium salts: Step 1: To a vigorously stirred solution of chiral diamine A (1.06 g, 5 mmol), K2CO3 (2.07 g, 15 mmol, 3 equiv.) in DCM (15 mL), was added the DCM (5 mL) solution of triphosgen (488 mg, 1.67 mmol) dropwise, stir at rt for 6 hours (monitored by TLC). After diamine A was completely consumed, reaction was quenched by water (20 mL) 93 Chapter3. The Experimental Procedures and extracted using DCM 3 times (30 mL x 3). The combined organic layer was washed by brine and dried by Na2SO4. Solvent was removed under reduced pressure and B was obtained as white to pale yellow needle type solid without further purification. Step 2: To a suspension of NaH (360 mg, 15 mmol, 3.0 equiv) in THF (10 mL) was added a solution of B (from step 1) in THF (10 mL). After 30 minutes, RBr or MeI (2.3 mL, 37 mmol, 3.7 equiv.) was added in one portion. After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite and the solution was collected and removed under reduced pressure and C was obtained by flash chromatography (silica gel, hexane/EA= 15:1), as a white solid, (2 steps, 80 to 90% overall yield). Step 3: To a solution of C2 (1mmol, 1 equiv.) in 15 mL xylenes was added lawesson reagent (809 mg, 2 mmol, 2 equiv.) under nitrogen atmosphere. Then the whole solution was heated to 140 oC for 48 hours and cool to room temperature. Upon the completion of the C2 on TLC, the whole solution was directly loaded on a column, use gravity to drain all the xylenes and use Hexane/EA= 50:1 to flush out the D as pale yellow solid. Further recrystalization in Hexane provided D as white solid with 60 to 80% yield. Step 4: A 100 mL round bottom flask was charged with a solution of D or C1(1.2 mmol, 1 equiv.) in toluene (10 mL) with a condenser under N2 atmosphere. (COCl)2 (3.1 mL, 36mmol, 30 equiv.) was added in one portion. The mixture was heated at 80 oC overnight until D or C1 was mostly reacted. Toluene was removed under reduced pressure and dried under vacuum line. Solid E1 or E2 was obtained for the next step 94 Chapter3. The Experimental Procedures without any further purification. Step 5: The above solid E1 or E2 was dissolved in dry MeCN (10 mL) under nitrogen atmosphere, and then the linker, such aspiperazine (34 mg, 0.4mmol, 0.3 equiv.), was added, followed by the addition of Et3N (0.42 mL, 3 mmol, 2.5 equiv.). Different substituted bis-guanidiums need different reaction temperature here: (1) For PTC 26a to PTC 26n in Chapter 1, the whole solution was heated to reflux for 12hours and cool to room temperature. (2) For sterically hindered bis-guanidiums, which includes PTC 26o to PTC 26r, the reaction was set up in a 100 mL sealed tube and heated at 110 oC for 12 hours and then turned off the heating and left it inside the oil bath for cooling. (3) For strong electron withdrawing groups substituted bis-guanidiums, the solution was heated at 50 oC for 8 hours and cool to room temperature. After cooling to room temperature, MeCN was removed under reduced pressure and 50 mL water was added. The mixture was extracted by DCM times (15 mL x 3). The combined organic layer was dried by Na2SO4. Solvent was removed under reduced pressure and PTC was obtained by flash chromatography (silica gel, DCM/Methanol= 100:1-20:1), as a white solid. (S,S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-one: white solid; 80% yield for 2 steps; 1H NMR (300 MHz, CDCl3): δ 7.34-7.32 (m, 6H), 7.14-7.11 (m, 4H), 4.07 (s, 2H), 2.69 (s, 6H); CDCl3) δ 161.7, 137.9, 128.7, 128.3, 127.2, 70.2, 29.9. 95 13 C NMR (126 MHz, Chapter3. The Experimental Procedures (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidaz olidine-2-thione: white solid, 89% yield; 1H NMR (500 MHz, CDCl3) δ 7.28 (tdd, J = 10.0, 7.4, 2.4 Hz, 4H), 7.02 (d, J = 1.5 Hz, 2H), 7.00 – 6.94 (m, 2H), 5.89 (d, J = 14.6 Hz, 1H), 4.25 (s, 1H), 3.75 (d, J = 14.6 Hz, 1H), 1.28 (s, 19H); 13 C NMR (126 MHz, CDCl3) δ 182.1, 151.0, 139.2, 135.1, 129.0, 128.5, 127.0, 122.9, 121.4, 77.2, 77.0, 76.8, 68.7, 49.7, 34.7, 31.4. (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-dimethyl-4,5-diphenyl-4,5-dihy dro-1H-imidazol-3-ium) chloride (PTC 26a): white solid, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.41 (q, J = 5.2 Hz, 12H), 7.32 – 7.18 (m, 8H), 4.65 (d, J = 9.4 Hz, 4H), 4.53 (s, 4H), 4.15 (d, J = 9.4 Hz, 4H), 3.25 (s, 12H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-tertbutylbenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26b): white solid, 40% yield; 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.27 (m, 12H), 7.21 (s, 4H), 7.09 – 6.99 (m, 8H), 6.96 (d, J = 1.2 Hz, 8H), 5.20 (d, J = 14.6 Hz, 4H), 4.79 (d, J = 14.6 Hz, 4H), 4.70 (d, J = 9.3 Hz, 4H), 4.48 (d, J = 9.5 Hz, 4H), 4.31 (s, 4H), 1.14 (s, 72H).13C NMR (126 MHz, CDCl3) δ 162.71, 151.37, 137.78, 131.97, 129.61, 129.19, 126.56, 123.48, 122.33, 70.35, 54.48, 49.07, 34.73, 31.32. 96 Chapter3. The Experimental Procedures (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-ter t-butyl-4-methoxybenzyl)-4,5-bis(4-(trifluoromethyl)phenyl) -4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26c): white solid, 33% yield; 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 8H), 7.23 (d, J = 8.0 Hz, 8H), 6.93 (s, 8H), 5.18 (d, J = 14.3 Hz, 4H), 4.98 (d, J = 9.0 Hz, 4H), 4.76 (d, J = 14.3 Hz, 4H), 4.56 (d, J = 9.5 Hz, 4H), 4.38 (s, 4H), 3.50 (s, 12H), 1.21 (s, 72H).13C NMR (126 MHz, CDCl3) δ 163.13, 159.93, 144.53, 141.34, 131.72, 127.66, 127.03, 126.64, 125.96, 124.59, 122.42, 69.94, 64.25, 54.90, 49.04, 35.63, 31.82. (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(naphthal en-1-ylmethyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26d): white solid, 41% yield; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 4H), 7.66 (dd, J = 17.4, 7.6 Hz, 8H), 7.39 (dt, J = 14.4, 6.9 Hz, 8H), 7.28 (s, 8H), 7.14 (dt, J = 14.4, 7.1 Hz, 12H), 6.94 (d, J = 7.2 Hz, 8H), 5.42 (d, J = 16.0 Hz, 4H), 5.04 (d, J = 16.1 Hz, 4H), 4.41 (d, J = 33.6 Hz, 12H), 2.37 (s, 8H). 97 Chapter3. The Experimental Procedures (4S,4'S,5S,5'S)-2,2'-(ethane-1,2-diylbis(methylazanediyl))bis(1 ,3-dibenzyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26e): white solid, 45% yield; 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.02 (m, 20H), 4.86 (d, J = 15.9 Hz, 2H), 4.61 (s, 2H), 4.46 – 4.39 (m, 3H), 3.33 (s, 4H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(naphthale n-2-ylmethyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26f): white solid, 28% yield;1H NMR (500 MHz, CDCl3) δ 7.70 – 7.56 (m, 16H), 7.40 – 7.26 (m, 24H), 7.18 – 7.08 (m, 8H), 5.21 (d, J = 15.8 Hz, 4H), 4.68 (d, J = 15.8 Hz, 4H), 4.59 (s, 4H), 4.38 (d, J = 9.6 Hz, 4H), 4.28 (d, J = 9.4 Hz, 4H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(2-bromo-3 ,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol3-ium)chloride (PTC 26g): white solid, 32% yield; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 2.0 Hz, 4H), 7.32 – 7.27 (m, 12H), 7.05 – 6.98 (m, 8H), 6.49 (d, J = 2.2 Hz, 4H), 5.29 (d, J = 13.5 Hz, 4H), 4.84 (d, J = 13.5 Hz, 4H), 4.77 (s, 8H), 3.85 (s, 4H), 1.43 (s, 36H), 0.99 (s, 36H). 98 Chapter3. The Experimental Procedures (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(4,5-diphenyl-1,3 -bis(3,4,5-trimethoxybenzyl)-4,5-dihydro-1H-imidazol-3-ium )chloride (PTC 26h): white solid, 42% yield; 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.29 (m, 12H), 7.12 (d, J = 7.0 Hz, 8H), 6.42 (s, 8H), 5.11 (d, J = 14.6 Hz, 4H), 4.77 (d, J = 14.6 Hz, 4H), 4.56 (s, 4H), 4.40 (s, 4H), 4.26 (s, 4H), 3.66 (s, 12H), 3.56 (s, 24H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(4-(tert-but yl)benzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26i): white solid, 44% yield;1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 6.0 Hz, 12H), 7.24 (s, 4H), 7.08 (dd, J = 11.7, 7.9 Hz, 16H), 5.02 (d, J = 15.8 Hz, 4H), 4.52 (s, 4H), 4.31 – 4.10 (m, 12H), 1.14 (s, 36H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(5-(tert-b utyl)-2-methylbenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol -3-ium) chloride (PTC 26j): white solid, 45% yield;1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 6.5 Hz, 12H), 7.11 – 7.04 (m, 12H), 6.96 (d, J = 7.9 Hz, 4H), 6.84 (s, 4H), 5.13 (d, J = 15.1 Hz, 4H), 4.79 (d, J = 15.0 Hz, 4H), 4.60 (d, J = 9.9 Hz, 4H), 4.36 (d, J = 13.9 Hz, 8H), 2.17 (s, 12H), 1.08 (s, 36H). 99 Chapter3. The Experimental Procedures (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-tertbutylbenzyl)-4,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-imida zol-3-ium) chloride (PTC 26k): white solid, 42% yield; 1H NMR (500 MHz, CDCl3) δ 7.23 (s, 2H), 7.02 – 6.95 (m, 8H), 6.81 (d, J = 8.6 Hz, 4H), 5.12 (d, J = 14.7 Hz, 2H), 4.73 (d, J = 14.9 Hz, 2H), 4.53 (s, 2H), 4.37 (d, J = 10.5 Hz, 2H), 4.31 (s, 2H), 3.76 (s, 6H), 1.17 (s, 36H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-ter t-butyl-2-chlorobenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidaz ol-3-ium) chloride (PTC 26l): white solid, 31% yield;1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 2.2 Hz, 4H), 7.32 – 7.28 (m, 12H), 7.01 – 6.93 (m, 8H), 6.56 (d, J = 2.1 Hz, 4H), 5.28 (d, J = 13.6 Hz, 4H), 4.71 (d, J = 16.8 Hz, 12H), 3.89 (s, 4H), 1.42 (s, 36H), 1.04 (s, 36H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-ter t-butylbenzyl)-4,5-di-p-tolyl-4,5-dihydro-1H-imidazol-3-ium) chloride (PTC 26m): white solid, 29% yield;1H NMR (500 MHz, CDCl3) δ 7.19 (s, 4H), 7.08 (d, J = 7.6 Hz, 8H), 6.92 (d, J = 10.1 Hz, 16H), 5.11 (d, J = 14.7 Hz, 4H), 4.78 (d, J = 14.8 Hz, 4H), 4.62 (d, J = 8.5 Hz, 4H), 4.39 (d, J = 9.4 Hz, 4H), 4.27 (s, 4H), 2.27 (s, 12H), 1.13 (s, 72H). 100 Chapter3. The Experimental Procedures (4S,4'S,5S,5'S)-2,2'-(pyrrolo[3,4-c]pyrrole-2,5(1H,3H,4H,6H)diyl)bis(1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihy dro-1H-imidazol-3-ium) chloride (PTC 26n): white solid, 45% yield;1H NMR (500 MHz, CDCl3) δ 7.30 (dd, J = 5.0, 1.6 Hz, 12H), 7.24 (s, 4H), 7.01 (dd, J = 6.8, 2.2 Hz, 8H), 6.87 (d, J = 1.4 Hz, 8H), 5.41 (d, J = 10.3 Hz, 4H), 5.08 (dd, J = 27.3, 12.4 Hz, 8H), 4.67 (d, J = 14.5 Hz, 4H), 4.24 (s, 4H), 1.12 (d, J = 5.8 Hz, 72H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-tertbutylbenzyl)-4,5-di(naphthalen-2-yl)-4,5-dihydro-1H-imidazo l-3-ium) chloride (PTC 26o): white solid, 18% yield; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 4H), 7.80 (d, J = 7.5 Hz, 4H), 7.76 (d, J = 7.5 Hz, 4H), 7.52 – 7.42 (m, 12H), 7.36 (d, J = 8.5 Hz, 4H), 7.16 (s, 4H), 6.99 (d, J = 1.1 Hz, 8H), 5.28 (d, J = 15.2 Hz, 4H), 4.93 (d, J = 14.8 Hz, 4H), 4.84 (d, J = 8.7 Hz, 4H), 4.65 (s, 4H), 4.59 (d, J = 9.5 Hz, 4H), 1.06 (s, 72H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-bis(tr imethylsilyl)benzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3 -ium) chloride (PTC 26p): pale yellow to white solid, 15% yield; 1H NMR (500 MHz, CDCl3) δ 7.44 (s, 4H), 7.29 (dd, J = 14.0, 12.5 Hz, 20H), 7.07 – 6.96 (m, 8H), 5.30 – 5.19 (m, 4H), 4.82 (dd, J = 26.7, 12.0 Hz, 8H), 4.49 (d, J = 9.5 Hz, 4H), 4.28 (s, 4H), 0.14 (s, 72H).13C NMR (126 MHz, CDCl3) δ 162.68, 101 Chapter3. The Experimental Procedures 156.39, 140.23, 138.23, 137.72, 134.69, 131.05, 129.69, 129.27, 126.42, 70.51, 54.43, 48.99, 29.59, -1.11. (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(4,5-bis(4-(tert-but yl)phenyl)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-dihydro-1H-imi dazol-3-ium) chloride (PTC 26q): white solid, 9% yield; 1H NMR (500 MHz, CDCl3) δ 6.82-7.35 (m, 28H), 4.21-5.18 (m, 20H), 1.28 (s, 36H), 1.12 (s, 72H). (4S,4'S,5S,5'S)-2,2'-((2S,5R)-2,5-dimethylpiperazine-1,4-diyl) bis(1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihydro -1H-imidazol-3-ium) chloride (PTC 26r): white solid, 14% yield;1H NMR (500 MHz, CDCl3) δ 7.24-7.30(m, 20H), 6.94 (s, 2H), 6.85 (s, 4H), 4.31-5.13 (m, 18H),1.85 (d, J = 6.3 Hz, 3H), 1.62 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.6 Hz, 72H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-bis(trif luoromethyl)benzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3ium) chloride (PTC 26s): white solid, 7% yield; 1H NMR (400 102 Chapter3. The Experimental Procedures MHz, CDCl3) δ 7.68 (s, 12H), 7.35 (d, J = 6.9 Hz, 12H), 7.15 – 7.08 (m, 8H), 5.58 (d, J = 16.3 Hz, 4H), 5.22 (d, J = 16.4 Hz, 4H), 4.93 (d, J = 9.1 Hz, 4H), 4.45 (s, 4H), 4.12 (d, J = 8.8 Hz, 4H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-ter t-butylbenzyl)-4,5-bis(4-nitrophenyl)-4,5-dihydro-1H-imidaz ol-3-ium) chloride (PTC 26t): yellow solid, 14% yield;1H NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 8.2, 1.4 Hz, 4H), 8.07 (d, J = 7.2 Hz, 4H), 7.60 (dd, J = 19.2, 11.2 Hz, 8H), 7.24 (s, 4H), 6.90 (d, J = 1.3 Hz, 8H), 5.21 (d, J = 14.9 Hz, 4H), 4.74 (dd, J = 30.7, 15.7 Hz, 12H), 4.47 (d, J = 9.5 Hz, 4H), 1.14 (s, 72H). (4S,4'S,5S,5'S)-2,2'-(piperazine-1,4-diyl)bis(1,3-bis(3,5-di-tert-b utylbenzyl)-4,5-bis(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-i midazol-3-ium) chloride (PTC 26u): white solid, 16% yield; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 8H), 7.24 (dd, J = 5.9, 3.9 Hz, 12H), 6.91 (d, J = 1.4 Hz, 8H), 5.21 (d, J = 14.5 Hz, 4H), 4.81 (dd, J = 21.8, 12.0 Hz, 8H), 4.51 (d, J = 9.5 Hz, 4H), 4.38 (s, 4H), 1.13 (s, 72H). 103 Chapter3. The Experimental Procedures (4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-2-(3,4-dihydroq uinoxalin-1(2H)-yl)-4,5-diphenyl-4,5-dihydro-1H-imida zol-3-ium chloride (PTC 26v): white to pale yellow solid, 50% yield; 1H NMR (500 MHz, CDCl3) δ 6.66-7.48 (m, 20H), 3.84-5,17 (m, 10H), 1.27 (s, 18H), 1.19 (s, 18H). 3.3 Representative Procedure for Asymmetric Mukaiyama Type SN2 Alkylation Reactions of Silyl Compounds and α-Bromoesters Method A: To a 1.5 mL vial added AgF (5 mg, 0.04 mmol), CsOAc (2.8 mg, 0.02 mmol) and PTC 16a (1.4 mg, 5 mol%). Then filled the vial with 0.15 mL 4-t-Bu-toluene and α-bromo methylacetate (4 μL, 0.04 mmol) and cool it to 0 oC, and stirred for 15 minutes. (Z)-68 (0.02 mmol) was added into the solution in one portion. The reaction mixture was stirred at 0 oC for another 24 hours and monitored by TLC. 104 Chapter3. The Experimental Procedures All the processes above were carried out in dark. When the reaction finished, all the solution was add to silica flash column and flushed with EA/hexane= 50:1. The product was colorless oil, 68% yield. Method B: To a 1.5 mL vial added TMAF (1.8 mg, 0.02 mmol) and PTC 16a (5 mol%). Then filled the vial with 0.3 mL toluene and α-bromo ester (0.04 mmol) and cool it to -60 oC, and stirred for 15 minutes. (Z)-68 (0.02 mmol) was added into the solution in one portion. The reaction mixture was stirred at -60 oC until the reaction was finished and monitored by TLC. When the reaction finished, all the solution was add to silica flash column and flushed with EA/hexane= 50:1. The product was colorless oil, 30~ 80% yield. (Z)-1-phenylprop-1-en-1-yl acetate: pale yellow liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.43 – 7.23 (m, 5H), 5.90 (q, J = 7.0 Hz, 1H), 2.31 (s, 3H), 1.72 (d, J = 7.0 Hz, 3H). Z/E =8:2. (Z)-trimethyl((1-phenylprop-1-en-1-yl)oxy)silane: colorless liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 5.36 (q, J = 6.8 Hz, 1H), 1.77 (d, J = 6.9 Hz, 3H), 0.11 (s, 9H).13C NMR (126 MHz, CDCl3) δ 149.91, 139.24, 128.03, 127.30, 125.22, 105.33, 11.69, 0.59. 105 Chapter3. The Experimental Procedures (Z)-((1-(3-chlorophenyl)prop-1-en-1-yl)oxy)trimethylsilane: colorless liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.45 (s, 1H), 7.34 (dt, J = 7.0, 1.7 Hz, 1H), 7.26 – 7.17 (m, 2H), 5.36 (q, J = 6.9 Hz, 1H), 1.74 (d, J = 6.9 Hz, 3H), 0.16 (s, 9H). (Z)-((1-(4-methoxyphenyl)prop-1-en-1-yl)oxy)trimethylsilane: colorless liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.42 – 7.37 (m, 2H), 6.85 – 6.79 (m, 2H), 5.21 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H), 0.14 (s, 9H). Z/E =10:1. (Z)-((1-(4-chlorophenyl)prop-1-en-1-yl)oxy)trimethylsilane: colorless liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 5.32 (q, J = 6.8 Hz, 1H), 1.73 (d, J = 6.9 Hz, 3H), 0.14 (s, 9H). (Z)-triethyl((1-phenylprop-1-en-1-yl)oxy)silane: colorless liquid, prepared according to published procedures;1H NMR (500 MHz, CDCl3) δ 7.49 – 7.42 (m, 2H), 7.27 (dt, J = 20.8, 7.1 Hz, 3H), 5.22 (q, J = 6.8 Hz, 1H), 1.76 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.62 (q, J = 7.9 Hz, 6H). Ethyl 2-(tosyloxy)acetate: colorless liquid, prepared according to 106 Chapter3. The Experimental Procedures published procedures; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). Benzyl 2-(nitrooxy)acetate: colorless liquid, prepared according to published procedures; 1H NMR (500 MHz, CDCl3) δ 7.50 – 7.28 (m, 5H), 5.25 (s, 2H), 4.93 (s, 2H). Methyl 3-methyl-4-oxo-4-phenylbutanoate: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 8.01 – 7.93 (m, 2H), 7.55 (ddd, J = 8.5, 2.4, 1.2 Hz, 1H), 7.46 (dd, J = 10.6, 4.7 Hz, 2H), 3.63 (s, 3H), 2.95 (dd, J = 16.8, 8.4 Hz, 1H), 2.45 (dd, J = 16.8, 5.8 Hz, 1H), 1.22 (d, J = 7.2 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 202.70, 172.79, 135.88, 133.06, 128.68, 128.44, 51.68, 37.23, 17.85. HPLC analysis: DAICEL OD-H 0.46x 25 cm (Hexane/IPA = 95:5, 0.5 mL/min, 254 nm, 25°C), 16.0 min, 23.1 min. Methyl 4-(4-chlorophenyl)-3-methyl-4-oxobutanoate: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 3.86 (ddd, J = 8.4, 7.1, 5.6 Hz, 1H), 3.61 (s, 3H), 2.93 (dd, J = 16.9, 8.6 Hz, 1H), 2.43 (dd, J = 16.9, 5.5 Hz, 1H), 1.18 (d, J = 7.2 Hz, 3H). HPLC analysis: DAICEL OD-H 0.46x 25 cm (Hexane/IPA = 95:5, 0.5 mL/min, 260 nm, 25°C), 14.4 min, 31.0 min. 107 Chapter3. The Experimental Procedures Methyl 4-(3-chlorophenyl)-3-methyl-4-oxobutanoate: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.98 – 7.88 (m, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.59 – 7.47 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 3.86 (ddd, J = 8.6, 7.2, 5.5 Hz, 1H), 3.62 (s, 3H), 2.95 (dd, J = 16.9, 8.7 Hz, 1H), 2.45 (dd, J = 16.9, 5.4 Hz, 1H), 1.19 (d, J = 7.2 Hz, 3H). HPLC analysis: DAICEL OD-H 0.46x 25 cm (Hexane/IPA = 95:5, 0.5 mL/min, 272 nm, 25°C), 13.1 min, 21.5 min. Methyl 4-(4-methoxyphenyl)-3-methyl-4-oxobutanoate: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.94 – 3.82 (m, 4H), 3.64 (s, 3H), 2.94 (dd, J = 16.7, 8.2 Hz, 1H), 2.44 (dd, J = 16.7, 5.9 Hz, 1H), 1.22 (d, J = 7.2 Hz, 3H). HPLC analysis: DAICEL AD-H 0.46x 25 cm (Hexane/IPA = 90:10, 1.0 mL/min, 290 nm, 25°C), 9.4 min, 11.1 min. Tert-butyl 3-methyl-4-oxo-4-phenylbutanoate: colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 12H), 7.35 (d, J = 6.9 Hz, 12H), 7.15 – 7.08 (m, 8H), 5.58 (d, J = 16.3 Hz, 4H), 5.22 (d, J = 16.4 Hz, 4H), 4.93 (d, J = 9.1 Hz, 4H), 4.45 (s, 4H), 4.12 (d, J = 8.8 Hz, 4H). HPLC analysis: Phenomenex Lux 5μ 0.46x 25 cm (Hexane/IPA = 95:5, 0.5 mL/min, 190 nm, 25°C), 13.5 min, 15.8 min. 108 Appendices Appendices 109 Appendices 110 Appendices 111 Appendices 112 Appendices 113 Appendices 114 Appendices 115 Appendices 116 Appendices 117 Appendices 118 Appendices 119 [...]... a new type of catalysts: full alkylated bis- guanidium PTCs (Figure 1.4) 29 Chapter 1 The Syntheses of Various Bis- Guanidium Salts Figure 1.4 From Pentanidium Salts to Bis- Guanidium Salts 1.2 Syntheses of Various Bis- Guanidium Salts Since the basic fragments of bis- guanidium salts are the same as those of pentanidium salts, the synthetic procedure is modified from that of pentanidium salts Standard... moderate yield and ee But there were some innovations in the catalyst design, one was the usage C3-symmetric structure rather than that of C2-symmetric; the other innovation was the great flexibility of the catalyst Bifunctional character of the catalyst was the key to ee induction (Scheme 1.13) 22 Chapter 1 The Syntheses of Various Bis- Guanidium Salts Scheme 1.13 Asymmetric Alkylation of 17 Catalyzed... Salts Chapt r 1: The Syntheses of Various Bis- Guanidium Salts 11 Chapter 1 The Syntheses of Various Bis- Guanidium Salts 1.1 Introduction to Asymmetric Phase-Transfer Catalysis 1.1.1 General Introduction Phase-transfer catalysts (PTCs) are chemical agents that facilitate the transfer of a molecule or ion from one reaction phase to another and in doing so can greatly accelerate the rate of heterogeneous... the hydroxyl group was protected with allyl group, the ee value could be further increased to 81% 18 Chapter 1 The Syntheses of Various Bis- Guanidium Salts Scheme 1.8 Asymmetric Monoalkylation of 17 Catalyzed by Alkaloid Derived PTC It had been 8 years until the next masterpiece in the area of phase-transfer catalysis came out In 1997, Lygo and Corey did the independent research on the asymmetric alkylation. .. provide the results as good as those in nonpolar solvents due to the larger polarity of solvents might destroy the dipole-dipole interaction between the substrate and the catalyst Further optimization 15 Chapter 1 The Syntheses of Various Bis- Guanidium Salts showed that the enantiomeric excess could be improved to 97% by using benzene as the solvent and PTC2 as the catalyst Also the catalyst loading might... source The author obtained excellent results in the model alkylation reaction.17 The author found that changing the counteranion of the catalyst from I- to BF4- could increase both ee and yield a little bit, which could be an evidence of counterion effect (Scheme 23 Chapter 1 The Syntheses of Various Bis- Guanidium Salts 1.15) Scheme 1.15 Tartrate-Derived Linear Chiral PTC Catalyzed Alkylation of 17 Inspired... Monoalkylation of 17 Starting from the commercially available chiral 1,1’-bi-2-naphthol, Maruoka and his coworkers successfully synthesized chiral spiroammonium salts PTC 15 and PTC 16 in 1999.13a These rigid C2-symmetric catalysts showed great efficiency in the asymmetric alkylation of 17 (Scheme 1.11) 20 Chapter 1 The Syntheses of Various Bis- Guanidium Salts Scheme 1.11 Asymmtric Alkylation of 17... Chapter 1 The Syntheses of Various Bis- Guanidium Salts were screened and 50% NaOH (aq.) gave the best results Different catalyst loadings might result in different reaction rates, but showed no direct relation with ee value of the product Scheme 1.7 Alkylation of Indanone Catalyzed by Alkaloid Derived PTC In 1989, inspired by Dolling’s previous result, Donnell modified the cinchona alkaloid and got the chiral... So we assumed that our full alkylated pentanidium salts should at least show better reaction rates than previous guanidine based PTCs Then we started to investigate these 26 Chapter 1 The Syntheses of Various Bis- Guanidium Salts pentanidium salts and their applications Figure 1.3 From Guanidine to Pentanidine and Pentanidium Salt Scheme 1.18 Synthesis of Full Methylated Pentanidium Salt As shown above... 1-chlorooctane (starting material and organic phase) with NaCN aqueous solution catalyzed by 12 Chapter 1 The Syntheses of Various Bis- Guanidium Salts hexadecyltributylphosphonium bromide (Scheme 1.1) The catalyst could distribute in both organic and aqueous layers, and exchanged the anions in the aqueous phase and took them back to the organic phase Without the phosphosium salt as the catalyst, there was no